Anti-viral method

ABSTRACT

A method of inhibiting an envelope virus selected from the group consisting of influenza bovine diarrheal, hepatitis C and tick borne encephalitis virus that udergoes hemagglutinin-mediated fusion with a host cell is disclosed which comprises administering to a virus-infected cell, a cell susceptible of infection or a mammal in need thereof, an effective amount of a compound as defined by Formula I in the specification.

This application is a continuation of Provisional Application Ser. No.60/016,906 filed May 6, 1996 which is a 371 of PCT/US97/07525 filed May2, 1997.

Influenza viruses cause an infectious disease for which there is noadequate therapeutic agent. The disadvantages of existing treatmentsinclude the onset of clinical resistance within thirty six hours and theineffectiveness of the agents against influenza B. Killed influenzavirus vaccines have been available for over sixty years. However, thesevaccines have not lessened the morbidity, mortality or severe financialloss caused by this disease. It follows that an agent which treats orprevents an influenza infection or is effective at preventing theclinical symptoms associated with an influenza infection will result ina significant benefit to society.

Currently, the only compounds approved for the therapeutic andprophylactic treatment of influenza infections are the adamantanes:amantadine and rimantadine. These compounds inhibit influenza A byinhibiting the function of the M2 ion channel activity of the virus.Amantadine is a potent in vitro inhibitor of influenza A virus asdemonstrated by standard antiviral assays such as the plaque reductionassay. Amantadine is effective in reducing the duration of fever andother systemic complaints including but not limited to myalgia (muscularache) and fatigue when administered to individuals infected withinfluenza A within forty-eight hours of the onset of clinical symptoms.It has also been observed that amantadine results in a one hundred-folddecrease of virus titer in the nasal washes of human volunteers infectedwith wild-type influenza virus which correlates with a dramatic decreasein fever score. Thus, in vitro influenza inhibition is predictive ofuseful in vivo effects, i.e. a reduction of the clinical symptomsassociated with the influenza infection.

The present invention derives from the fact that influenza is anenveloped virus which dictates that the virus envelope must be fusedwith the endosomal membrane of the host cell in order to initiate theprocess of introducing its genetic information into the cell. Becausethis process is common to all enveloped viruses, it is an attractivetarget for antiviral chemotherapy. Examples of envelope viruses whichare inhibited according to the present invention include influenza,bovine diarrheal, hepatitis C, tick borne encephalitis and the like. Thefusion domain of the envelope glycoprotein of influenza, hemagglutinin(HA) has been well characterized. See, White J. M., Annu. Rev. Physiol.vol. 52, pages 675-697 (1990) which is herein incorporated by reference.

Influenza virus HA provides at least two distinct functions: 1)recognition of the host cell receptor, i.e., sialic acid residues onglycoconjugates, and 2) fusion of the viral envelope with the endosomalmembrane. Both functions are essential for the propagation of influenzavirus in vitro and in vivo. During viral maturation, monomeric HA isinserted into a lipid bilayer, post-translationally modified andoligomerized into a trimer of identical subunits (trimeric HA). Theinfectivity of the progeny virus is contingent upon a site-specificcleavage of HA by host cell protease(s). This cleavage results in theformation of two polypeptide chains, HA1 and HA2, which remainassociated by non-covalent interactions as well as by an intermolecularand intramolecular disulfide bonds.

It has been established that influenza HA has two functionally relevantconformations. One conformation (Form A) exists as a metastablestructure at neutral pH and mediates receptor recognition. Followingreceptor mediated binding to the host cell, the virus is transported tothe endosomal compartment where it encounters an acidic environment. Thelow pH triggers a dramatic structural rearrangement of HA (Form A) whichresults in the formation of the other, more stable conformation of HA(Form B).

Form B of HA is required for fusion of the virus envelope with theendosomal membrane. It is the structural rearrangement from Form A toForm B of HA that allows the fusion domain of HA to directly interactwith the endosomal membrane enabling the release of viral geneticinformation into the host cell cytoplasm. These considerations lendthemselves to the development of a strategy for antiviral interventionbased on the abrogation of HA-mediated fusion of virus-host membranes.

The present invention relates to methods for using the compoundsdisclosed in the application for the treatment or prevention of viralinfection and the resultant symptoms. These compounds, theirpharmaceutically acceptable salts and the pharmaceutical compositionscan be used alone or in combination with other antivirals,immunomodulators, antibiotics or vaccines.

The present invention relates to a method of treating or preventing avirus infection where the virus is an envelope virus that undergoeshemagglutinin-mediated fusion with the host cell which comprisesadministering to a virus infected cell, a cell susceptible of infectionor a mammal in need thereof an effective amount of a compound of formulaI: ##STR1## wherein:

R is hydrogen or R and R⁶ combine to form a bond;

R⁰ and R¹ are independently hydrogen, hydroxy, C₁ -C₆ alkyl, C₁ -C₆alkoxy, hydroxy(C₁ -C₆ alkyl), sulfhydryl, sulfamyl, --SO₂ --Cl,--S--C(O)--N(CH₃)₂, amino, C₁ -C₄ alkylamino, di(C₁ -C₄ alkyl)amino, C₁-C₄ alkylsulfonylamino, di(C₁ -C₄ alkylsulfonyl)amino --X⁰ --O--C(O)--C₁-C₄ alkyl, --O--(X¹)_(i) --X², --C(O)--X³, --N--C(O)--R² or --O----R³ ;

X⁰ is a bond or divalent(C₁ -C₆ alkyl);

X¹ is an amino acid;

X² is hydrogen or an amino protecting group;

i is 1, 2 or 3;

X³ is C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halo(C₁ -C₆ alkyl), hydroxy(C₁ -C₆alkyl) or phenyl;

R² is C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halo(C₁ -C₄ alkyl), hydroxy(C₁ -C₄alkyl), phenyl, p-methoxy-phenyl, p-fluoro-phenyl, naphthyl, pyridyl,piperidinyl, thiazolyl, oxazolyl, thienyl, furyl, tetrahydrofuryl orcyclohexyl;

R³ is C₁ -C₆ alkenyl, --CH₂ --R^(3a), --C(O)--R^(3b), --C(S)--R^(3c),--C(CH₃)₂ C(O)NH₂, phenyl or a group of the formula: ##STR2##

R^(3a) is phenyl, p-fluorophenyl, pyridyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, N--(C₁ -C₄ alkoxycarbonyl)piperidinyl,N-(trifluoromethyl)-piperidinyl, thiazolyl, oxazolyl, imidazolyl,isothiazolyl, isooxazolyl, quinolyl, isoquinolyl, thienyl, furyl,tetrahydrothienyl, tetrahydrofuryl, cyclohexyl, cyclopentyl, cyclopropylor naphthyl;

R^(3b) is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, N--(C₁-C₄ alkoxycarbonyl)piperidinyl, N-(trifluoromethyl)piperidinyl,benzyloxy, pyridylmethyloxy, C₁ -C₆ alkoxy, halo(C₁ -C₄ alkoxy), amino,C₁ -C₄ alkylamino or di(C₁ -C₄ alkyl)amino;

R^(3c) is amino, C₁ -C₄ alkylamino or di(C₁ -C₄ alkyl)amino;

R^(3d) is oxygen, hydroximino, hydrazino or ═CHZ;

Z is hydrogen, C₁ -C₄ alkyl, halogen, di(C₁ -C₄ alkyl)amino, C₁ -C₄alkoxycarbonyl, carbamoyl(C₁ -C₄ alkyl), N-(C₁ -C₄ alkyl)carbamoyl orN,N-di(C₁ -C₄ alkyl)carbamoyl;

R^(3e) is hydrogen, nitro or trifluoromethyl;

X is a bond or --(CH₂)--;

R⁴ is hydrogen, hydroxy, amino, C₁ -C₄ alkylamino, di(C₁ -C₄alkyl)amino, C₁ -C₄ alkoxy, ═O, --O--S (CH₃)₂ C(CH₃)₃, C₂ -C₆alkanoyloxy, N--(C₂ -C₆ alkanoyl)amino, ═N--R⁵ or R⁴ and R⁶ combine toform a bond;

R⁵ is hydroxy, amino, C₁ -C₄ alkylamino, di(C₁ -C₄ alkyl)amino, C₁ -C₄alkoxy, pyridylmethoxy, benzyloxy, piperazinyl, N-(methyl)piperazinyl or--O--CH₂ --C(O)--R^(5a) ;

R^(5a) is hydroxy or C₁ -C₄ alkoxy;

R⁶ is hydrogen, halo, C₁ -C₄ alkyl or ═O;

R⁷ is hydrogen or C₁ -C₄ alkyl;

R⁸ is hydroxy, halo, C₁ -C₆ alkoxy, pyrrolidinyl, piperidinyl,piperazinyl, 4-methyl-piperazinyl, morpholinyl or --N(R⁹)--R¹⁰ ;

R⁹ is hydrogen or methyl;

R¹⁰ is -(divalent C₁ -C₆ alkyl)--R^(10a) ;

R^(10a) is pyridyl,

with the proviso that R⁶ cannot combine with both R⁴ and R to form abond;

or a pharmaceutically acceptable salt thereof.

All temperatures stated herein are in degrees Celsius (°C.). All unitsof measurement employed herein are in weight units except for liquidswhich are in volume units.

The term "halo" represents chloro, fluoro, bromo or iodo.

The term "C₁ -C₆ alkyl" represents a straight or branched alkyl chainhaving from one to six carbon atoms. Typical C₁ -C₆ alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyland the like. The term "C₁ -C₆ alkyl" includes within its definition theterm "C₁ -C₄ alkyl."

The term "halo(C₁ -C₆)alkyl" represents a straight or branched alkylchain having from one to six carbon atoms with 1, 2 or 3 halogen atomsattached to it. Typical halo(C₁ -C₆)alkyl groups include chloromethyl,2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl,3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.

The term "hydroxy(C₁ -C₆)alkyl" represents a straight or branched alkylchain having from one to six carbon atoms with an hydroxy group attachedto it. Typical hydroxy(C₁ -C₆)alkyl groups include hydroxymethyl,2-hydroxyethyl, 1-hydroxyisopropyl, 2-hydroxypropyl, 2-hydroxybutyl,3-hydroxyisobutyl, hydroxy-t-butyl, hydroxypentyl and the like.

The term "C₁ -C₄ alkylamino" represents a straight or branchedalkylamino chain having from one to four carbon atoms attached to anamino group. Typical C₁ -C₄ alkyl-amino groups include methylamino,ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino andthe like.

The term "di(C₁ -C₄)alkylamino" represents a straight or brancheddialkylamino chain having two alkyl chains, each having independentlyfrom one to four carbon atoms attached to a common amino group. Typicaldi(C₁ -C₄)alkylamino groups include dimethylamino, ethylmethylamino,methylisopropyl-amino, t-butylisopropylamino, di-t-butylamino and thelike.

The term "C₁ -C₆ alkoxy" represents a straight or branched alkyl chainhaving from one to six carbon atoms attached to an oxygen atom. TypicalC₁ -C₆ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,butoxy, t-butoxy, pentoxy and the like. The term "C₁ -C₆ alkoxy"includes within its definition the term "C₁ -C₄ alkoxy".

The term "C₂ -C₆ alkenyl" represents a straight or branched alkenylchain having from two to six carbon atoms. Typical C₂ -C₆ alkenyl groupsinclude ethenyl, propenyl, isopropenyl, buten-2-yl, t-butenyl,penten-1-yl, hexen-3-yl, 3-methylpentenyl and the like.

The term "C₁ -C₄ alkoxycarbonyl" represents a straight or branchedalkoxy chain having from one to four carbon atoms attached to a carbonylmoiety. Typical C₁ -C₄ alkoxy-carbonyl groups include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,t-butoxycarbonyl and the like.

The term "carbamoyl(C₁ -C₄)alkyl" represents a straight or branchedalkyl chain having from one to four carbon atoms with a carbamoyl groupattached to it. Typical carbamoyl(C₁ -C₄)alkyl groups includecarbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylisopropyl,carbamoylbutyl and carbamoyl-t-butyl and the like.

The term "N-(C₁ -C₄)alkylcarbamoyl" represents a straight or branchedalkyl chain having from one to four carbon atoms attached to thenitrogen atom of a carbamoyl moiety. Typical N-(C₁ -C₄ alkyl)carbamoylgroups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-t-butylcarbamoyl and the like.

The term "N,N-di(C₁ -C₄ alkyl)carbamoyl" represents a straight orbranched alkyl chain having a straight or branched C₁ -C₄ alkyl chainattached to each of the nitrogen atoms on a carbamoyl moiety. TypicalN-(C₁ -C₄)alkylcarbamoyl groups include N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N-propyl-N-butylcarbamoyl,N,N-diisopropylcarbamoyl, N-methyl-N-butylcarbamoyl and the like.

The term "C₁ -C₄ alkylsulfonylamino" represents a straight or branchedalkyl group having from one to four carbon atoms attached to asulfonylamino moiety. Typical C₁ -C₄ alkylsulfonylamino groups includemethylsulfonyl-amino, ethylsulfonylamino, propylsulfonylamino,isopropylsulfonyl-amino, butylsulfonylamino, isobutylsulfonylamino,sec-butylsulfonylamino, and t-butylsulfonylamino.

The term "di(C₁ -C₄ alkylsulfonyl)amino" represents two C₁ -C₄alkylsulfonyl moieties attached to an amino moiety. Typical di(C₁ -C₄alkylsulfonyl)amino groups include methylmethylsulfonylamino,ethylmethylsulfonylamino, propylethylsulfonylamino,isopropylmethylsulfonylamino, t-butylethylsulfonylamino,butylbutylsulfonylamino and the like.

The term "C₂ -C₆ alkanoyl" represents a straight or branched alkyl chainhaving from one to five carbon atoms attached to a carbonyl moiety.Typical C₂ -C₆ alkanoyl groups include ethanoyl, propanoyl,isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl,3-methylpentanoyl and the like.

The term "C₂ -C₆ alkanoyloxy" represents a straight or branched alkylgroup having from one to five carbon atoms attached to a carbonyloxymoiety. Typical C₂ -C₆ alkanoyloxy groups include ethanoyloxy,propanoyloxy, isopropanoyloxy, butanoyloxy, isobutanoyloxy,sec-butanoyloxy, t-butanoyloxy, pentanoyloxy and the like.

The term "C₂ -C₆ alkanoylamino" represents a straight or branched alkylgroup one to five carbon atoms attached to a carbonylamino moiety.Typical C₂ -C₆ alkanoylamino groups include ethanoylamino,propanoylamino, isopropanoylamino, butanoyl-amino, isobutanoylamino,sec-butanoylamino, t-butanoylamino, pentanoylamino and the like.

As mentioned above, the invention includes the pharmaceuticallyacceptable salts of the compounds defined by formula I. Althoughgenerally neutral, a compound of this invention can possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein, refers tosalts of the compounds of the above formula which are substantiallynon-toxic to living organisms. Typical pharmaceutically acceptable saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a mineral or organic acid or an inorganic base. Suchsalts are known as acid addition and base addition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like.

Examples of such pharmaceutically acceptable salts are the sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,γ-hydroxybutyrate, glycollate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate,mandelate and the like. Preferred pharmaceutically acceptable acidaddition salts are those formed with mineral acids such as hydrochloricacid and hydrobromic acid, and those formed with organic acids such asmaleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is not of a critical nature, so long as thesalt as a whole is pharmacologically acceptable and as long as thecounterion does not contribute undesired qualities to the salt as awhole.

The term "amino-protecting group" as used in the specification refers tosubstituents of the amino group commonly employed to block or protectthe amino functionality while reacting other functional groups on thecompound. Examples of such amino-protecting groups include formyl,trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,iodoacetyl groups, or urethane-type blocking groups such asbenzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy-carbonyl("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like;benzoylmethylsulfonyl, 2-nitrophenylsulfenyl, diphenylphosphine oxideand like amino-protecting groups. The species of amino-protecting groupemployed is not critical so long as the derivatized amino group isstable to the condition of subsequent reactions) on other positions ofthe intermediate molecule and can be selectively removed at theappropriate point without disrupting the remainder of the moleculeincluding any other amino-protecting group(s). Preferredamino-protecting groups are t-butoxycarbonyl (t-Boc), allyloxycarbonyland benzyloxycarbonyl (CbZ). Further examples of groups referred to bythe above terms are described by J. W. Barton, "Protective Groups inOrganic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,1973, Chapter 2, and T. W. Greene, "Protective Groups in OrganicSynthesis", John Wiley and sons, New York, N.Y., 1981, Chapter 7.

The term "carboxy-protecting group" as used in the specification refersto substituents of the carboxy group commonly employed to block orprotect the carboxy functionality while reacting other functional groupson the compound. Examples of such carboxy-protecting groups includemethyl, p-nitrobenzyl, p-methylbenzyl, p-methoxy-benzyl,3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl,benzhydryl, 4, 4'-dimethoxy-benzhydryl,2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl,4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl,2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl,2,2,2-trichloroethyl, β-(dibutylmethylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferredcarboxy-protecting groups are allyl, benzyl and t-butyl. Furtherexamples of these groups are found in E. Haslam, "Protective Groups inOrganic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,1973, Chapter 5, and T. W. Greene, "Protective Groups in OrganicSynthesis", John Wiley and Sons, New York, N.Y., 1981, Chapter 5.

The compounds used in the present invention have at least two asymmetriccenters as denoted by the asterisks in the formula below: ##STR3##

The following stereoisomers are preferred: ##STR4##

Preferred compounds used in the claimed method are those compounds offormula I where:

R⁰ is hydrogen, hydroxy, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, hydroxy(C₁ -C₆alkyl), --X⁰ --O--C(O)--C₁ -C₄ alkyl, --O--(X¹)_(i) --X², --C(O)--X³ or--O--R³ ;

R¹ is hydrogen, hydroxy, C₁ -C₆ alkoxy, sulfhydryl, sulfamyl, --SO₂--Cl, amino, di(C₁ -C₄ alkylsulfonyl)amino --C(O)--X³, --N--C(O)--R² or--O--R³ ;

X⁰ is a bond or divalent(C₁ -C₆ alkyl);

X¹ is an amino acid;

X² is hydrogen or an amino protecting group;

i is 1 or 2;

X³ is C₁ -C₆ alkyl;

R² is hydroxy(C₁ -C₄ alkyl);

R³ is C₁ -C₆ alkenyl, --CH₂ --R^(3a), --C(O)--R^(3b), --C(S)--R^(3c),--C(CH₃)₂ C(O)NH₂ or a group of the formula: ##STR5##

R^(3a) is phenyl, p-fluorophenyl, pyridyl, piperidinyl, piperazinyl ormorpholinyl;

R^(3b) is piperidinyl, piperazinyl, morpholinyl, N-(C₁ -C₄alkoxycarbonyl)piperidinyl, N-(trifluoromethyl)piperidinyl, halo(C₁ -C₄alkoxy) or di(C₁ -C₄ alkyl)amino;

R^(3c) is di(C₁ -C₄ alkyl)amino;

R^(3d) is oxygen or hydroximino;

R^(3e) is hydrogen, nitro or trifluoromethyl;

X is a bond;

R⁴ is hydrogen, hydroxy, amino, ═O, C₂ -C₆ alkanoyloxy, ═N--R⁵,--OSi(CH₃)₂ or R⁴ and R⁶ combine to form a bond;

R⁵ is hydroxy, amino, di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkoxy,pyridylmethoxy, N-(methyl)piperazinyl or --O--CH₂ --C(O)--R^(5a) ;

R⁶ is hydrogen, chloro, bromo, methyl or ═O;

R⁷ is hydrogen or methyl;

R⁸ is hydroxy, chloro, methoxy, 4-methylpiperazinyl or --N(R⁹)--R¹⁰ ;

R⁹ is hydrogen;

R¹⁰ is --CH₂ --R^(10a) ; and

R^(10a) is pyridyl;

or a pharmaceutically acceptable salt thereof.

Of these compounds, more preferred are those compounds of formula Iwhere:

R⁰ is hydrogen, hydroxy, C₁ -C₆ alkoxy, --O--(X₁)_(i) --X², --X⁰--O--C(O)--C₁ -C₄ alkyl or --O--R³ ;

R¹ is hydrogen, hydroxy, C₁ -C₆ alkoxy or --O--R³ ;

X⁰ is a bond;

X¹ is an amino acid;

X² is hydrogen or an amino protecting group;

i is 1 or 2;

R³ is C₁ -C₆ alkenyl, --CH₂ --R^(3a) or --C(O)--R^(3b) ;

R^(3a) is p-fluorophenyl or pyridyl;

R^(3b) is piperidinyl;

R⁴ is hydrogen, hydroxy, ═O or ═N--R⁵ ;

R⁵ is hydroxy, dimethylamino or N-(methyl)piperazinyl;

R⁶ is hydrogen, bromo or ═O;

R⁷ is methyl; and

R⁸ is methoxy;

or a pharmaceutically acceptable salt thereof.

Of these compounds, even more preferred are those compounds of formula Iwhere:

R is hydrogen;

R⁰ is hydrogen, hydroxy, C₁ -C₄ alkoxy, --O--(X¹)_(i) --X²,--O--C(O)methyl or --O--R³ ;

R¹ is hydrogen, hydroxy, C₁ -C₄ alkoxy or --O--R³ ;

X¹ is glycine, alanine or valine;

X² is hydrogen, t-butoxycarbonyl or benzyloxycarbonyl;

R⁴ is ═O or ═N--R⁵ ;

R⁵ is hydroxy;

R⁶ is hydrogen;

or a pharmaceutically acceptable salt thereof.

The compounds of formula I may be prepared according to procedures knownin the art. For example, the following Reaction Schemes may be used,alone or in combination to provide the desired compounds. Once areaction is complete, the intermediate compound may be isolated byprocedures well-known in the art; for example, the compound may becrystallized and then collected by filtration, or the reaction solventmay be removed by extraction, evaporation or decantation. Theintermediate compound may be further purified, if desired, by commontechniques such as crystallization or chromatography over solid supportssuch as silica gel or alumina, before carrying out the next step of thereaction scheme.

The compounds of formula I where R⁴ is ═O or ═N--R may be preparedaccording to the procedures shown below in Reaction Scheme I. ##STR6##where Reactions I.4A and 4B represent alternative reactions that followReaction 1.3 and Reaction I.4C is an alternative reaction followingReaction I.2.

Reaction scheme I is accomplished by carrying out reactions 1-4 insequential order. Reaction I.1 is carried out by oxidizing a compound offormula IA, for example, by reaction with chromium trioxide in an aceticacid/water mixture, to provide the corresponding ketone. The chromiumtrioxide is generally employed in an amount ranging from equimolarproportions to about a 4 molar excess relative to the compound offormula IA, preferably in about a 2-4 molar excess. The aceticacid/water mixture is generally a 10:1 to a 2:1 mixture of acetic acidto water, preferably about 4:1. The reaction is generally substantiallycomplete after about 1 to 10 hours when conducted at a temperature offrom about 23° C. to about 60° C. The reaction is preferably conductedat a temperature of from about 23° C. to about 30° C. for about 5 to 10hours.

In Reaction I.2, the ketone obtained from Reaction I.1 is reacted withbromine in a suitable solvent such as diethyl ether, tetrahydrofuran ordimethoxyethane, to provide a mixture of bromoketones which are thenseparated using standard separation techniques such as chromatography.These isomerically pure bromoketones are then used to prepare variousisomerically pure compounds of formula I. The bromine is generallyemployed in an amount ranging from about equimolar proportions to abouta 2 molar excess relative to the ketone reactant, preferably in about a1-1.5 molar excess. Solvent choice is not critical so long as thesolvent employed is inert to the ongoing reaction and the reactants aresufficiently solubilized to effect the desired reaction. The reaction isgenerally substantially complete after about 1 to 3 hours when conductedat a temperature of from about 23° C. to about 30° C. The reaction ispreferably conducted at room temperature for about 1 to 1.5 hours.

Alternatively, the ketone obtained from Reaction I.1 is reacted with asilylating agent in the presence of a base in a suitable solvent such asmethylene chloride, diethyl ether or tetrahydrofuran to provide thecorresponding silylated enol ether. Preferred bases include 2,6-lutidineand collidine. A preferred silylating agent is t-butyldimethylsilyltrifluoromethanesulfonate. The silylating agent is generally employed inan amount ranging from about equimolar proportions to about a 2 molarexcess relative to the ketone reactant, preferably in about a 1-1.5molar excess. Solvent choice is not critical so long as the solventemployed is inert to the ongoing reaction and the reactants aresufficiently solubilized to effect the desired reaction. The reaction isgenerally substantially complete after about 30 minutes to 2 hours whenconducted at a temperature of from about 0° C. to about 50° C. Thereaction is preferably conducted at a temperature of from about 10° C.to about 25° C. for about 30 minutes to about 1 hour.

The silylated enol ether is then reacted with bromine substantially asdescribed above with the exception that the reaction is carried out inthe presence of acetic acid. Typical solvents suitable for use in thisreaction include any organic solvent such as methylene chloride, diethylether or tetrahydrofuran. Solvent choice is not critical so long as thesolvent employed is inert to the ongoing reaction and the reactants aresufficiently solubilized to effect the desired reaction.

In Reaction I.3, the bromoketone is reduced, for example by reactionwith zinc dust and sodium acetate in glacial acetic acid, to provide thecorresponding ketones. The zinc is generally employed in an amountranging from about equimolar proportions to about a 4 molar excessrelative to the ketone reactant, preferably in about a 1.5-3 molarexcess. The sodium acetate is generally employed in an amount rangingfrom about 0.6 molar equivalents to about 1.2 molar equivalents relativeto the ketone reactant. The reaction is generally substantially completeafter about 1 to 10 hours when conducted at a temperature of from about60° C. to the reflux temperature of the mixture. The reaction ispreferably conducted at reflux temperature for about 1 to 2 hours.

Alternatively, hydroxylamine hydrochloride is reacted with sodiumacetate in a suitable solvent such as ethanol. The sodium acetate isgenerally employed in an amount ranging from about 1.1 molar equivalentsto about a 50 molar excess relative to the hydroxylamine. The reactionis generally substantially complete after about 1 to 72 hours whenconducted at a temperature of from about 25° C. to about 80° C. Thereaction is preferably conducted at a temperature in the range of fromabout 25° C. to about 30° C. for about 5 to 24 hours.

In Reaction I.4A, the ketone obtained from Reaction I.3 is reacted withhydroxylamine hydrochloride in a mixture of methanol, water and aceticacid to provide the desired oxime compound. The hydroxylaminehydrochloride is generally employed in an amount ranging from aboutequimolar proportions to about a 4 molar excess relative to the ketonereactant, preferably in about a 1.3-3 molar excess. The ratio ofmethanol to water to acetic acid is generally 10-20:1:0.1, preferably15:1:0.1 (by volume?). The reaction is generally substantially completeafter about 1 hour to about 2 days when conducted at a temperature offrom about 40° C. to the reflux temperature of the mixture. The reactionis preferably conducted at reflux temperature for about 1 to 6 hours.

In Reaction I.4B, the ketone obtained from Reaction I.3 is reacted withan hydrazine hydrochloride such as 1-amino-4-methylpiperazine,1,1-dimethylhydrazine or hydrazine in the presence of a base in an inertsolvent at a temperature of from about 25° C. to 80° C. for 2 to 24hours. Typical bases include sodium acetate, potassium hydroxide,triethylamine and the like. Suitable solvents include ethanol,isopropanol and dimethylformamide. Solvent choice is not critical solong as the solvent employed is inert to the ongoing reaction and thereactants are sufficiently solubilized to effect the desired reaction.

In Reaction I.4C, the compounds obtained from Reaction I.2 where R ishydrogen may be eliminated by reacting the bromo ketone reactant with abase such as sodium methoxide in methanol, sodium ethoxide in ethanol,or triethylamine to provide the unsaturated compounds of formula I whereR and R⁶ are combined to form a bond. The base is generally employed inabout a 2-4 molar excess relative to the bromo ketone reactant,preferably in about a 3 molar excess. The reaction is generallysubstantially complete after about 3 to 9 hours when conducted at atemperature of from about 40° C. to the reflux temperature of themixture. The reaction is preferably conducted at reflux temperature 3 to5 hours.

The phenyl moiety of the compounds of formula I prepared above may besubstituted according to Reaction Scheme II, as follows. ##STR7## whereR⁰ ' and R¹ ' are independently hydrogen or --C(O)CH₃ ; and R⁰ " and R¹" are independently hydrogen or hydroxy.

In Reaction II.1, the compound of formula I where R⁰ and R¹ are eachhydrogen is subjected to a Friedel-Crafts acylation by reacting thecompound of formula I with an acid halide, in the presence of a catalystin an inert solvent such as carbon disulfide. The acid halide isgenerally employed in an amount ranging from about equimolar proportionsto about a 1.5 molar excess relative to the compound of formula I,preferably in about a 1.1-1.3 molar excess. Preferred acid halidesinclude acetyl chloride, acetyl bromide or the like. Preferred catalystsinclude aluminum trichloride, aluminum tribromide or the like. Solventchoice is not critical so long as the solvent employed is inert to theongoing reaction and the reactants are sufficiently solubilized toeffect the desired reaction. The reaction is generally substantiallycomplete after about 1 to 10 hours when conducted at a temperature offrom about 50° C. to the reflux temperature of the mixture. The reactionis preferably conducted at reflux temperature for about 1 to 2 hours.

In Reaction II.2, the acylated compound of formula I obtained fromReaction II.1 is oxidized to provide the corresponding phenol in a twostep reaction. First, the acyl moiety is reacted with a peracid in thepresence of an acid catalyst in an inert solvent such as dimethoxyethaneto provide the corresponding ester with is then reacted with sodiumbicarbonate in an alcohol/water mixture to provide the desired phenol.

The peracid is generally employed in an amount ranging from aboutequimolar proportions to about a 2 molar excess relative to the acylmoiety, preferably in about a 1-1.3 molar excess. The amount of catalysttypically employed is in the range of 0.005-0.04 equivalents relative tothe acyl moiety. A preferred peracid is metachloro-peroxybenzoic acid. Apreferred catalyst is p-toluenesulfonic acid. Solvent choice is notcritical so long as the solvent employed is inert to the ongoingreaction and the reactants are sufficiently solubilized to effect thedesired reaction. The reaction is generally substantially complete afterabout 1 to 10 hours when conducted at a temperature of from about 50° C.to the reflux temperature of the mixture. The reaction is preferablyconducted at reflux temperature for about 1 to 3 hours.

The resultant ester is typically refluxed with a base in amethanol/water mixture for about 1 to 7 hours to provide the desiredphenol compound. Preferred bases include sodium bicarbonate, sodiumcarbonate, sodium hydroxide or potassium hydroxide or the like. The baseis generally employed in an excess, for example from about a 1 molarexcess to about a 6 molar excess relative to the ester moiety,preferably in about a 2-5 molar excess

The phenol compounds obtained from Reaction Scheme II may be used toprepare various substituted compounds of formula I, as described below.

For example, the hydroxy moiety may be alkylated by reacting the phenolcompound with a suitable alkylating agent in the presence of a base inan inert solvent. Examples of bases include triethylamine, diisopropylethylamine, sodium hydride and potassium carbonate. Typical solventsinclude methylene chloride, tetrahydrofuran, dimethylformamide and thelike. Solvent choice is not critical so long as the solvent employed isinert to the ongoing reaction and the reactants are sufficientlysolubilized to effect the desired reaction. Suitable alkylating agentsinclude iodomethane, allyl iodide, p-fluorophenyl bromide,3-bromomethyl-pyridine and 2-fluorobenzophenone and the like. Thereaction is generally substantially complete after about 1 to 20 hourswhen conducted at a temperature of from about 0° C. to 170° C. Thereaction is preferably conducted at a temperature of from about 25° C.to about 80° C. for about 4 to 16 hours.

Alternatively, the hydroxy moiety may be alkylated by reacting thephenol with an alcohol in the presence of triphenylphosphine and asuitable activating agent in an inert solvent, such as tetrahydrofuranor ethylene glycol dimethyl ether. Examples of suitable activatingagents include diethyl azodicarboxylate, dimethyl azodicarboxylate,diisopropyl azodicarboxylate and the like. Examples of alcohols include3-pyridyl carbinol, N-t-butoxycarbonyl-3-piperidinemethanol and thelike. The reaction is generally substantially complete after about 0.5to 2 hours when conducted at a temperature of from about 0° C. to 85° C.The reaction is preferably conducted at a temperature of from about 25°C. to about 70° C. for about 30 minutes to 1 hour.

The hydroxy moiety may be converted to an ester or a carbonate byreacting the phenol with an acylating agent in the presence of a base inan inert solvent, such as methylene chloride, tetrahydrofuran ordimethylformamide. Typical bases include triethylamine, diisopropylethylamine, sodium hydride and the like. Typical acylating agentsinclude N-(t-butoxycarbonyl)-4-chlorocarbonyl piperdine,2,2,2-trichloroethyl chloroformate,N-(t-butoxycarbonyl)-hydroxybenzotriazole amino esters. The reaction isgenerally substantially complete after about 1 to 20 hours whenconducted at a temperature of from about 0° C. to 60° C. The reaction ispreferably conducted at a temperature of from about 10° C. to about 25°C. for about 1 to 5 hours.

The hydroxy moiety may be converted to the corresponding aniline in athree step reaction. First, the phenol is reacted with a suitablysubstituted amide such as 2-methyl-2-bromo-propanamide in the presenceof a base such as sodium hydride or triethylamine in an inert solvent,such as dioxane or tetrahydrofuran at a temperature of 25° C. to 100° C.to provide the corresponding amido-ether. This amido-ether is thenreacted with sodium hydride in an inert solvent such asdimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone or amixture thereof at temperatures ranging from 25° C. to 145° C. toprovide the rearranged amido-alcohol. Finally, the amido-alcohol isreacted with an acid, such as hydrochloric acid in dioxane at 50° C. to100° C. to provide the desired aniline.

The aniline may be converted to the corresponding sulfonamide byreacting the aniline with a sulfonyl chloride such as methanesulfonylchloride or isopropylsulfonyl chloride in the presence of a base, suchas triethylamine, diisopropyl ethylamine or sodium hydride at atemperature of from about 0° C. to 50° C. in an inert solvent, such asmethylene chloride, tetrahydrofuran or dimethylformamide.

The hydroxy moiety may be converted to a thiophenol in a three stepreaction. First the phenol is reacted with a thio-carbamoyl (for exampledimethylthiocarbamoyl chloride) in the presence of a base in an suitablesolvent, such as water or dimethylformamide at a temperature rangingfrom 25° C. to 50° C. for 1 to 3 hours to provide the oxo-thiocarbamate.Typical bases include potassium hydroxide, triethylamine and the like.The oxo-thiocarbamate is converted to the correspondingthio-oxocarbamate compound by isolating and heating the neat solid toits melting point. Finally, the thio-oxocarbamate is reacted with abase, such as potassium hydroxide or sodium hydroxide in an alcoholicsolvent, such as methanol or ethanol at a temperature of 20° C. to 80°C. for 20 minutes to 1 hour to provide the corresponding thiophenol.

The thiophenol may be converted to the corresponding sulfonamides byreacting the thiophenol with an oxidizing agent (for example, potassiumnitrate) in an inert solvent such as acetonitrile, followed by theaddition of a chlorinating agent (for example, sulfuryl chloride) attemperatures ranging from 0° C. to 25° C. to provide a mixture ofsulfonyl chlorides which are separable using standard chromatographictechniques. These sulfonyl chlorides may be converted to the desiredsulfonamides by reaction with an appropriately substituted amine such asammonium hydroxide, methylamine, isopropylamine or benzylamine at atemperature of from about 0° C. to 40° C. in an inert solvent suchtetrahydrofuran.

The hydroxy moiety may be converted to the corresponding amino esters byreacting the phenol with an amino protected amino acid in the presenceof a coupling reagent and a catalyst in an inert solvent such as diethylether, tetrahydrofuran or methylene chloride. Preferred amino protectinggroups include t-butoxycarbonyl or benzyloxycarbonyl. The amino reactantis generally employed in equimolar proportions to a slight excess (1.3equivalents) relative to the phenol reactant in the presence of anequimolar quantity to a slight excess (1.5 equivalents) of the couplingreagent. Typical coupling agents include dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP), N,N'-diethylcarbodiimide, carbonyldiimidazole,bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) orN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) and the like.Preferred coupling agents include DCC and BOP. Typical catalysts includeDMAP and 4-pyrrolopyridine. The reaction is substantially complete in 1to 10 hours when carried out at a temperature of from about -30° C. toabout 35° C., preferably from about 0° C. to about 25° C.

The starting materials used in the procedures detailed above may beobtained commercially or prepared according to procedures known in theart. For example, methyl O-methylpodocarpate having the followingstereochemistry may be obtained from Aldrich Chemical Company: ##STR8##

In addition, the compound(s) of formula IA, below may be preparedsubstantially in accordance with the procedure detailed in Ohta andOhmuri, Chem. Pharm. Bull. (Tokyo), vol 5, page 91 (1957). The isomericmix of compounds may be separated using standard separation techniques.Preferably, these isomers are obtained using the bromination methodologydescribed above in Reaction Scheme I.

The compounds) of formula IA may also be used to prepare other isomersusing the procedure detailed in Pelletier et al., Tetr. Lett. page 4179(1971). For example, heating the compound(s) of formula IA in a highboiling point solvent such as triethylene glycol dimethylether(triglyme) results in a compound of formula IB as follows: ##STR9## Theresultant mixture of isomers is then separated using standard proceduressuch as recrystallization or column chromatography or may be subjectedto the bromination methodology described above in Reaction Scheme I.

The following Preparations and Examples further illustrate specificaspects of the present invention. It is to be understood, however, thatthese examples are included for illustrative purposes only and are notintended to limit the scope of the invention in any respect and shouldnot be so construed.

PREPARATION 1 N-t-Butoxycarbonyl-4-carboxy-piperidine

To a solution of 1.0 g (7.74 mmol) of 4-carboxy-piperidine in 40 ml of a1:1 water/dioxane mixture, was added 3.2 g (23.2 mmol) of potassiumcarbonate (K₂ CO₃) followed by 2.1 ml (9.3 mmol) ofdi(t-butyl)dicarbonate (BOC₂ O). After 2 hours, the mixture was dilutedwith methylene chloride (CH₂ Cl₂). The resulting layers were separatedand the organic layer was dried over sodium sulfate (Na₂ SO₄), filteredand concentrated in vacuo. The crude material was recrystallized from a3:1 hot EtOAc/hexanes (EtOAc/hexanes) mixture.

Yield: 1.52 g (86%).

PREPARATION 2 N-t-Butoxycarbonyl-3 -hydroxymethyl-piperidine

To a mixture of 5.0 g (43.4 mmol) of 3-hydroxymethyl-piperidine in 200ml of CH₂ Cl₂, was added 6.05 ml (43.4 mmol) of triethylamine (Et₃ N),followed by 9.8 ml (43.4 mmol) of (BOC₂ O). The reaction mixture wasstirred for 1 hour at room temperature and then washed with 75 ml of a0.1N hydrochloric acid solution (HCl), dried over Na₂ SO₄, filtered andthen concentrated in vacuo.

Yield: 7.1 g (76%).

PREPARATION 3 2-Bromo-2-methyl-propanamide

To a cold (0° C.) solution of 11 ml (89 mmol) of2-bromo-2-methyl-propionyl bromide in 25 ml of hexane, was added 24 mlof concentrated ammonium hydroxide (NH₄ OH), slowly. The reactionmixture was stirred for 20 minutes resulting in the formation of a whiteprecipitate. This precipitate was isolated by filtration, washed threetimes with water (H₂ O) and then dried in vacuo to provide 9.1 g of awhite solid which was redissolved in 600 ml of hot chloroform (CHCl₃)and filtered immediately. The filtrate was combined with 2100 ml ofhexane and cooled overnight.

Yield: 6.1 g of crystals (41%).

EXAMPLE 1 A. Methyl O-methyl podocarpate

The compound is prepared from podocarpic acid according to the method ofShaw, JOC, vol. 39, p. 1968, (1974), herein incorporated by reference.

¹ H NMR (300 MHz, CDCl₃) : δ6.98 (d, J=8Hz, 1H); 6.83 (d, J=4Hz, 1H);6.70 (dd, J=4,8HZ, 1H); 3.78 (s, 3H); 3.67 (s, 3H); 2.80 (m, 2H); 2.25(m, 3H); 2.0 (m, 2H); 1.6 (m, 2H); 1.42 (m, 1H); 1.30 (s, 3H); 1.12 (m,1H) and 1.05 (s, 3H).

MS: m/e 288 (M+'). ##STR10##

To a solution of 2.0 g (6.62 mmol) of the compound of Example 1A in 10ml of 1,1,2 trichloroethane, was added 1.0 ml (7.0 mmol) ofiodotrimethylsilane. The reaction mixture was heated to 70° C., reactedfor 10 minutes, cooled, diluted with 150 ml of a 3:1 hexane/diethylether (hexane/Et₂ O) mixture and then washed with a saturated sodiumbicarbonate solution (NaHCO₃), dried over Na₂ SO₄, filtered andconcentrated in vacuo.

Yield: 1.51 g of a light tan solid (83%).

¹ H NMR (300 MHz, CDCl₃): δ6.9 (d, J=8Hz, 1H); 6.72 (d, J=4Hz, 1H); 6.58(dd, J=4,8Hz, 1H); 4.55 (s, 1H); 3.63 (s, 3H); 2.75 (m, 2H); 2.20 (m,3H); 1.95 (m, 2H); 1.57 (m, 2H); 1.4 (m, 1H); 1.25 (s, 3H); 1.08 (m, 1H)and 1.01 (s, 3H).

MS: m/e 274 (M+). ##STR11##

The compound was prepared substantially in accordance with the proceduredetailed in Example 1B, using 1.0 g (3.31 mmol) of the compound ofExample 1A, 1.0 ml (7.0 mmol) of iodotrimethylsilane and 5 ml of1,1,2-trichloroethane, with the exception that the saturated NaHCO₃ washwas acidified to pH 2. The desired compound was then extracted with CH₂Cl₂, and the extracts were dried over Na₂ SO₄, filtered and thenconcentrated in vacuo to provide 100 mg of a white solid (11%).

¹ H NMR (300 MHz, CDCl₃): δ6.93 (d, J=8Hz, 1H); 6.73 (d, J=4Hz, 1H); 6.6(dd, J=4,8Hz, 1H); 2.78 (m, 2H); 2.22 (m, 3H); 2.03 (m, 2H); 1.58 (m,2H); 1.40 (m, 1H); 1.35 (s, 3H); 1.15 (s, 3H) and 1.10 (m, 1H).

Note: 780 mg of the compound of Example 1B was recovered.

EXAMPLE 2 ##STR12##

To a solution of 100 mg (0.35 mmol) of the compound of Example 1B in 2ml of dimethylformamide (DMF), was added 62 mg (0.45 mmol) of K₂ CO₃,followed by 42 μl (0.45 mmol) of isopropyl bromide. The reaction mixturewas stirred for 2 hours at room temperature and then combined with anadditional 180 mg (1.3 mmol) of K₂ CO₃ and 130 μl (1.38 mmol) ofisopropyl bromide. This mixture was stirred for 24 hours and thendiluted with a 1:1 hexane/Et₂ O mixture. The resultant layers wereseparated and the organic layer was washed sequentially with H₂ O and0.1N HCl, dried over Na₂ SO₄, filtered and then concentrated in vacuo toprovide an oily residue which was purified using flash chromatography(SiO₂, eluent of 5% EtOAc in hexane).

Yield: 51 mg.

¹ H NMR (300 MHz, CDCl₃): δ6.95 (d, J=8HZ, 1H); 6.8 (d, J=4Hz, 1H); 6.65(dd, J=4,8Hz, 1H); 4.47 (m, 1H); 3.64 (s, 3H); 2.78 (m, 2H); 2.22 (m,3H); 1.97 (m, 2H); 1.58 (m, 2H); 1.40 (m, 1H); 1.32 (d, J=6Hz, 3H); 1.28(d, J=6Hz, 3H); 1.10 (m, 1H) and 1.07 (s, 3H).

The compounds described in Examples 3-5 were prepared substantially inaccordance with the procedure detailed in Example 2, using the shownstarting materials.

EXAMPLE 3 ##STR13##

100 mg (0.35 mmol) of the compound of Example 1B, 242 mg (1.75 mmol) ofK₂ CO₃ and 169 μl (1.40 mmol) of allylbromide in 2 ml of DMF.

Yield: 75 mg (65%).

¹ H NMR (300 MHZ, CDCl₃): δ6.97 (d, J=8HZ, 1H); 6.83 (d, J=4HZ, 1H);6.68 (dd, J=4, 8Hz, 1H); 6.07 (m, 1H); 5.35 (m, 2H); 4.50 (m, 2H); 3.68(s, 3H); 2.78 (m, 2H); 2.23 (m, 3H); 1.98 (m, 2H); 1.58 (m, 2H); 1.40(m, 1H); 1.28 (S. 3H); 1.10 (m, 1H) and 1.03 (s, 3H).

EXAMPLE 4 ##STR14##

100 mg (0.35 mmol) of the compound of Example 1B, 93 mg (0.67 mmol) ofK₂ CO₃ and 81 μl (0.68 mmol) of 4-fluorobenzyl chloride in 2 ml of DMF.

Yield: 87 mg (63%).

¹ H NMR (300 MHz, CDCl₃): δ7.4 (m, 2H); 7.08 (m, 2H); 6.98 (d, J=8HZ,1H); 6.88 (d, J=4Hz, 1H); 6.74 (dd, J=4,8Hz, 1H); 4.98 (s, 2H); 3.68 (s,3H); 2.78 (m, 2H); 2.23 (m, 3H); 1.96 (m, 2H); 1.58 (m, 2H); 1.40 (m,1H); 1.28 (s, 3H); 1.10 (m, 1H) and 1.03 (s, 3H).

EXAMPLE 5 ##STR15##

100 mg (0.35 mmol) of the compound of Example 1B, 180 mg (1.30 mmol) ofK₂ CO₃ and 107 mg (0.65 mmol) of 2-picolyl chloride hydrochloride in 2ml of DMF.

Yield: 35 mg (26%).

¹ H NMR (300 MHz, CDCl₃): δ8.58 (d, J=6Hz, 1H); 7.70 (m, 1H); 7.52 (d,J=6Hz, 1H); 7.20 (m, 1H); 6.95 (d, J=8Hz, 1H); 6.89 (d, J=4Hz, 1H); 6.74(dd, J=4,8Hz, 1H); 5.18 (s, 2H); 3.64 (s, 3H); 2.77 (m, 2H); 2.20 (m,3H); 1.97 (m, 2H); 1.55 (m, 2H); 1.27 (s, 3H); 1.08 (m, 1H) and 1.0 (s,3H).

EXAMPLE 6 ##STR16##

A solution of 6.58 g (65.04 mmol) of chromium trioxide in 70 ml of a 4:1acetic acid (AcOH)/H₂ O mixture was added to a mixture of 7.0 g (23.15mmol) of the compound in Example 1A in 70 ml of AcOH. The reactionmixture was stirred for 18 hours resulting in the precipitation of asolid. This solid was isolated by filtration, washed with H₂ O, dried invacuo, redissolved in 75 ml of hot isopropanol (iPrOH) and filtered hot.The filtrate was combined with 225 ml of H₂ O and cooled to 5° C. for 16hours to provide crystals which were isolated by filtration, washed withH₂ O and dried in vacuo at 45° C.

Yield: 6.31 g (86%).

¹ H NMR (300 MHz, CDCl₃): δ8.04 (d, J=8Hz, 1H); 6.88 (d, J=4Hz, 1H);6.82 (dd, J=8,4Hz, 1H); 3.87 (s, 3H); 3.72 (s, 3H); 3.18 (m, 1H); 2.95(m, 1H); 2.33 (m, 2H); 2.05 (m, 2H); 1.72 (m, 1H); 1.55 (m, 1H); 1.25(s, 3H); 1.16 (m, 1H) and 1.11 (s, 3H).

MS: m/e 316 (M+).

Elemental Analysis for C₁₉ H₂₄ O₄ :

Calcd: C, 72.13; H, 7.65;

Found: C, 72.15; H, 7.79.

EXAMPLE 7 ##STR17##

To a solution of 316 mg (1.0 mmol) of the compound of Example 6 in 3.0ml of absolute ethanol (EtOH), was added 80 mg (1.15 mmol) orhydroxylamine hydrochloride followed by 94 mg (1.15 mmol) of sodiumacetate (NaOAc). The reaction mixture was stirred for 65 hours at roomtemperature and then concentrated in vacuo to provide a solid which waspartitioned between Et₂ O and H₂ O. The resultant layers were separatedand the organic layer was dried over Na₂ SO₄, filtered and concentratedin vacuo to provide a solid. This solid was redissolved in 0.5 ml of Et₂O and 8 ml of hot hexane and then cooled to 0° C. resulting in theformation of crystals.

Yield: 282 mg (85%).

¹ H NMR (300 MHz, CDCl₃): δ8.0 (s, 1H); 7.88 (d, J=8Hz, 1H); 6.88 (d,J=4Hz, 1H); 6.78 (dd, J=4,8Hz, 1H); 3.82 (s, 3H); 3.74 (s, 3H); 3.45 (m,1H); 3.07 (m, 1H); 2.30 (m, 2H); 2.02 (m, 1H); 1.72 (m, 2H); 1.57 (m,1H); 1.35 (s, 3H); 1.13 (m, 1H) and 1.0 (s, 3H).

MS: m/e 331 (M+).

Elemental Analysis for C₁₉ H₂₅ NO₄ :

Calcd: C, 68.86; H. 7.60; N, 4.23;

Found: C, 69.12; H, 7.69; N, 4.21.

EXAMPLE 8 ##STR18##

To a hot (100° C.) solution of 426 mg (1.48 mmol) of the compound inExample 1B in 3.0 ml of collidine, was added 0.45 ml (2.66 mmol) of2-fluorobenzophenone, 415 mg (3.0 mmol) of K₂ CO₃ and 444 mg (5.58 mmol)of copper (II) oxide (CuO). The reaction mixture was then heated to 171°C. and reacted for 16 hours. After cooling, the mixture was diluted with50 ml of Et₂ O, washed with 20 ml of 1N HCl, dried over Na₂ SO₄,filtered and then concentrated in vacuo to provide a brown oil. This oilwas purified using radial chromatography (4000 micron plate, gradienteluent of 75-100% CH₂ Cl₂ in hexane).

Yield: 352 mg (51%).

¹ H NMR (300MHz, CDCl₃): δ7.82 (d, J=6Hz, 2H); 7.45 (m, 5H); 7.18 (m,1H); 6.90 (m, 2H); 6.75 (m, 1H); 6.58 (m, 1H); 3.67 (s, 3H); 2.77 (m,2H); 2.20 (m, 2H); 1.95 (m, 3H); 1.60 (m, 1H); 1.47 (m, 1H); 1.35 (m,1H); 1.27 (s, 3H); 1.02 (m, 1H) and 0.95 (s, 3H).

MS: m/e 469 (M+).

Elemental Analysis for C₃₁ H₃₂ O₄ :

Calcd: C, 79.46; H, 6.88;

Found: C, 79.53; H, 7.06.

EXAMPLE 9 ##STR19##

The compound was prepared substantially in accordance with the proceduredetailed in Example 6, using 260 mg (0.56 mmol) of the compound ofExample 8, 158 mg (1.56 mmol) of chromium trioxide in a 3.05 mlAcOH/0.34 ml H₂ O mixture.

Yield: 231 mg (86%).

¹ H NMR (300 MHz, CDCl₃): δ7.90 (d, J=8Hz, 1H); 7.75 (m, 2H); 7.55 (m,3H); 7.35 (m, 3H); 7.10 (d, J=8Hz, 1H); 6.72 (d, J=4Hz, 1H); 6.62 (dd,J=4,8Hz, 1H); 3.70 (s, 3H); 3.15 (m, 1H); 2.93 (m, 1H); 2.30 (m, 1H);2.0 (m, 3H); 1.63 (m, 1H); 1.38 (m, 1H); 1.23 (s, 3H); 1.10 (m, 1H) and1.0 (s, 3H).

MS: m/e 483 (M+).

Elemental Analysis for C₃₁ H₃₀ O₅ :

Calcd: C, 77.16; H, 6.27;

Found: C, 76.96; H, 6.29.

EXAMPLE 10 ##STR20##

The compound was obtained from the Bader chemical collection, AldrichChemical Company.

¹ H NMR (300 MHz, CDCl₃): δ8.38 (d, J=4Hz, 1H) ; 8.23 (dd, J=4,8Hz, 1H);7.87 (d, J=6Hz, 2H); 7.60 (m, 1H); 7.48 (t, J=6Hz, 2H); 7.03 (d, J=8Hz,1H); 6.85 (m, 2H); 6.68 (dd, J=4, 8Hz, 1H); 3.64 (s, 3H); 2.80 (m, 2H);2.22 (m, 2H); 1.98 (m, 3H); 1.55 (m, 2H); 1.33 (m, 1H); 1.26 (s, 3H);1.07 (m, 1H) and 0.97 (s, 3H).

MS: m/e 513 (M+).:

Elemental Analysis for C₃₁ H₃₁ NO₆ :

Calcd: C, 72.50; H, 6.08; N, 2.73

Found: C, 72.40; H, 6.11; N, 2.66.

EXAMPLE 11 ##STR21##

The compound was prepared substantially in accordance with the proceduredetailed in Example 7, using 150 mg (0.311 mmol) of the compound ofExample 9, 22 mg (0.311 mmol) of hydroxylamine hydrochloride and 26 mg(0.311 mmol) of NaOAc in 3.0 ml of EtOH. The crude material was purifiedusing radial chromatography (2000 micron plate, eluent of 5% EtOAc inCH₂ Cl₂).

Yield: 138 mg (89%).

¹ H NMR (300 MHZ, CDCl₃): δ7.78 (m, 3H); 7.45 (m, 5H); 7.25 (mn, 1H);7.0 (d, J=8Hz, 1H); 6.75 (d, J=4Hz, 1H); 6.62 (dd, J=4,8Hz, 1H); 3.70(s, 3H); 3.4 (m, 1H); 3.02 (m, 1H); 2.25 (m, 1H); 1.98 (m, 2H); 1.63 (m,2H); 1.37 (m, 1H); 1.30 (s, 3H); 1.08 (m, 1H) and 0.92 (s, 3H).

MS: m/e 497 (M+). ##STR22##

The compound was isolated from the reaction mixture described in Example11A.

Yield: 5 mg.

¹ H NMR (300 MHz, CDCl₃): δ7.65 (d, J=8Hz, 1H); 7.50 (m, 2H); 7.30 (m,6H); 7.02 (d, J=8Hz, 1H); 6.90 (d, J=4Hz, 1H); 6.78 (dd, J=4,8Hz, 1H);3.69 (s, 3H); 3.4 (m, 1H); 3.02 (m, 1H); 2.2 (m, 2H); 1.95 (m, 1H); 1.63(m, 2H); 1.42 (m, 1H); 1.30 (s, 3H); 1.08 (m, 1H) and 0.95 (s, 3H).

MS: m/e 512 (M+). ##STR23##

The compound was isolated from the reaction mixture described in Example11A.

Yield: 4 mg

¹ H NMR (300 MHz, CDCl₃): δ7.68 (t, J=8Hz, 1H); 7.50 (m, 1H); 7.30 (m,5H); 6.85 (m, 3H); 6.58 (d, J=4Hz, 1H); 6.44 (dd, J=4,8Hz, 1H); 3.68 (s,3H); 3.38 (m, 1H); 3.0 (m, 1H); 2.24 (m, 1H); 2.0 (m, 2H); 1.63 (m, 2H);1.37 (m, 1H); 1.30 (s, 3H); 1.07 (m, 1H) and 0.92 (s, 3H).

MS: m/e 512 (M+).

EXAMPLE 12 ##STR24##

The compound was prepared substantially in accordance with the proceduredetailed in Example 8, using 100 mg (0.347 mmol) of the compound ofExample 1B, 98 mg (0.423 mmol) of 2-bromobiphenyl, 97 mg (0.702 mmol) ofK₂ CO₃ and 70 mg (0.88 mmol) of CuO in 1.5 ml of collidine. The crudematerial was purified using column chromatography (eluent of 30% hexanein CH₂ Cl₂).

Yield: 81 mg (53%).

¹ H NMR (300 MHz, CDCl₃): δ7.58 (m, 2H); 7.25 (m, 6H); 6.95 (m, 2H);7.88 (d, J=4Hz, 1H); 6.70 (dd, J=4,8Hz, 1H); 3.64 (s, 3H); 2.78 (m, 2H);2.15 (m, 3H); 1.95 (m, 2H); 1.55 (m, 2H); 1.35 (m, 1H); 1.25 (s, 3H);1.05 (m, 1H) and 0.97 (s, 3H).

MS: m/e 440 (M+).

EXAMPLE 13 ##STR25##

The compound was prepared substantially in accordance with the proceduredetailed in Example 8, using 500 mg (1.74 mmol) of the compound ofExample 1B, 950 mg (3.54 mmol) of2-fluoro-5-(trifluoromethyl)benzo-phenone, 500 mg (3.62 mmol) of K₂ CO₃,and 350 mg (4.35 mmol) of CuO in 8.0 ml collidine. The crude materialwas purified using radial chromatography (4000 micron plate, eluent of25% hexane in CH₂ Cl₂).

Yield: 670 mg (72%).

¹ H NMR (300 MHz, CDCl₃): δ7.84 (d, J=8HZ, 2H); 7.75 (m, 1H); 7.57 (m,2H) ; 7.45 (t, J=8Hz, 2H); 6.97 (d, J=8Hz, 1H) ; 6.89 (d, J=8Hz, 1H);6.80 (d, J=4Hz, 1H); 6.62 (dd, J=4,8Hz, 1H); 3.62 (s, 3H); 2.78 (m, 2H);2.20 (m, 2H); 1.98 (m, 3H); 1.55 (m, 2H); 1.30 (m, 1H); 1.25 (s, 3H);1.08 (m, 1H) and 0.96 (s, 3H).

MS: m/e 536 (M+).

EXAMPLE 14 ##STR26##

The compound was prepared substantially in accordance with the proceduredetailed in Example 6, using 75 mg (0.14 mmol) of the compound ofExample 13, 40 mg (0.40 mmol) of chromium trioxide in a 0.85 ml ACOH/0.1ml H₂ O mixture.

Yield: 49 mg (64%).

¹ H NMR (300 MHz, CDCl₃): δ7.95 (d, J=6Hz, 1H); 7.77 (m, 3H); 7.58 (m,1H); 7.42 (t, J=6Hz, 2H); 7.12 (d, J=8Hz, 1H); 6.80 (d, J=4Hz, H); 6.70(dd, J=4,8Hz, 1H); 3.68 (s, 3H); 3.18 (m, 1H); 2.95 (m, 1H); 2.30 (m,1H); 2.0 (m, 3H); 1.67 (m, 1H); 1.40 (m, 1H); 1.25 (s, 3H); 1.12 (m, 1H)and 1.03 (s, 3H).

MS: m/e 550 (M+).

EXAMPLE 15 ##STR27##

To a solution of 200 mg (0.694 mmol) of the compound of Example 1B in5.0 ml of CH₂ Cl₂, was added 0.372 ml (2.10 mmol) ofdiisopropylethylamine and 86 mg (0.70 mmol) of 4-dimethylamino pyridinefollowed by a mixture containing 480 mg (2.10 mmol) of the compound ofPreparation 1, 0.207 ml (2.56 mmol) of pyridine and 0.170 ml (2.33 mmol)of thionyl chloride in 5.0 ml of CH₂ Cl₂. The reaction mixture wasstirred at room temperature for 30 minutes, diluted with CH₂ Cl₂, washedsequentially with 1N HCl and a saturated NaHCO₃ solution, dried over Na₂SO₄, filtered and then concentrated in vacuo to provide a tan foam. Thisfoam was purified using radial chromatography (2000 micron plate,gradient eluent of 10% hexane in CH₂ Cl₂ to 25% EtOAc in CH₂ Cl₂).

Yield: 280 mg (81%).

¹ H NMR (300 MHz, CDCl₃): δ7.02 (d, J=8HZ, 1H); 6.90 (d, J=4HZ, 1H);6.77 (dd, J=4,8HZ, 1H): 4.08 (m, 2H); 3.65 (s, 3H) ; 2.90 (m, 3H) ; 2.75(m, 3H); 2.20 (m, 3H) ; 1.98 (m, 4H); 1.78 (m, 2H); 1.6 (m, 1H); 1.45(s, 9H); 1.40 (m, 1H); 1.28 (s, 3H); 1.08 (m, 1H) and 1.0 (s, 3H).

MS: m/e 499 (M+).

EXAMPLE 16 ##STR28##

To a solution of 250 mg (0.50 mmol) of the compound in Example 15 in 1.0ml of CH₂ Cl₂, was added 0.160 ml (1.0 mmol) of triethylsilane and 1.0ml of trifluoroacetic acid (CF₃ COOH). The reaction mixture was stirredfor 30 minutes at room temperature, diluted with 15 ml of acetonitrile(CH₃ CN) and then concentrated in vacuo to provide 231 mg of a tansolid. Then, 200 mg of this solid was dissolved in 20 ml of CH₂ Cl₂,washed with a saturated NaHCO₃ solution, dried over Na₂ SO₄, filteredand concentrated in vacuo.

Yield: 170 mg (98%).

¹ H NMR (300 MHZ, CDCl₃):δ7.02 (d, J=8Hz, 1H); 6.92 (d, J=4Hz, 1H); 6.78(dd, J=4,8Hz, 1H); 3.63 (s, 3H); 3.17 (m, 2H); 2.75 (m, 5H); 2.20 (m,3H); 1.98 (m, 4H); 1.75 (m, 2H); 1.58 (m, 2H); 1.40 (m, 1H); 1.27 (s,3H); 1.08 (m, 1H) and 1.0 (s, 3H).

MS: m/e 400 (M+).

EXAMPLE 17 ##STR29##

To a solution of 160 mg (0.4 mmol) of the free base of the compound ofExample 16 in 4.0 ml of a 3:1 Et₂ O/hexane mixture, was added 26 μl (0.4mmol) of methanesulfonic acid.

Yield: 198 mg of a solid (quantitative).

¹ H NMR (300 MHz, CDCl₃):δ8.43 (bs, 1H); 8.20 (bs, 1H) ; 6.75 (d, J=8Hz,1H); 6.60 (d, J=4Hz, 1H); 6.45 (dd, J=4,8Hz, 1H); 3.55 (s, 3H); 3.20 (m,2H); 2.90 (m, 2H); 2.58 (m, 3H); 2.30 (s, 3H); 2.10 (m, 3H); 1.93 (m,4H); 1.65 (m, 2H); 1.47 (m, 2H); 1.24 (m, 1H); 1.17 (s, 3H); 1.08 (m,1H) and 0.88 (s, 3H).

EXAMPLE 18 ##STR30##

To a solution of 160 mg (0.324 mmol) of the compound in Example 17 in3.0 ml CH₂ Cl₂, was added 100 μl (0.712 mmol) of Et₃ N and 50 μl (0.356mmol) of trifluoroacetic anhydride. The reaction mixture was stirred for15 minutes at room temperature, diluted with 30 ml of EtOAc,sequentially washed with 10 ml of 0.2N HCl, 10 ml of a saturated NaHCO₃solution and 10 ml brine, dried over NaSO₄, filtered and thenconcentrated in vacuo.

Yield: 130 mg (81%).

¹ H NMR (300 MHz, CDCl₃):δ7.03 (d, J=8Hz, 1H); 6.91 (d, J=4Hz, 1H); 6.78(dd, J=4,8Hz, 1H); 4.37 (m, 1H); 4.0 (m, 1H); 3.64 (s, 3H); 3.35 (m,1H); 3.15 (m, 1H); 2.82 (m, 3H); 2.28 (m, 1H); 2.18 (m, 4H); 1.95 (m,3H); 1.50 (m, 4H); 1.25 (s, 3H); 1.08 (m, 1H) and 1.0 (s, 3H).

EXAMPLE 19 ##STR31##

To a solution of 470 mg (1.63 mmol) of the compound of Example 1B in12.0 ml of a 1:2 Et₂ O/CH₂ Cl₂ mixture, was added 0.237 ml (1.70 mmol)of Et₃ N and 0.224 ml (1.63 mmol) of 2,2,2-trichloroethyl chloroformate.The reaction mixture was stirred at room temperature for 20 minutes,diluted with 50 ml of Et₂ O, sequentially washed with 15 ml of H₂ O, 15ml of 0.2N HCl, 15 ml of NaCO₃ and 15 ml of brine, dried over Na₂ SO₄,filtered and then concentrated in vacuo to provide an oily residue. Thisresidue was purified using flash chromatography (SiO₂, eluent of 30%hexane in CH₂ Cl₂).

Yield: 620 mg (82%).

¹ H NMR (300MHz, CDCl₃):δ7.08 (m, 2H); 6.93 (m, 1H); 4.87 (s, 2H); 3.67(s, 3H); 2.90 (m, 1H); 2.78 (m, 1H); 2.23 (m, 3H); 2.00 (m, 2H); 1.58(m, 2H); 1.42 (m, 1H); 1.30 (s, 3H); 1.12 (m, 1H) and 1.03 (s, 3H).

MS: m/e 463 (M+).

EXAMPLE 20 ##STR32##

The compound was prepared substantially in accordance with the proceduredetailed in Example 6, using 620 mg (1.33 mmol) of the compound ofExample 19, 405 mg (4.0 mmol) of chromium trioxide in a 8.1 ml AcOH/0.9ml H₂ O.

Yield: 540 mg (85%).

¹ H NMR (300MHz, CDCl₃): δ8.02 (d, J=8Hz, 1H); 6.90 (d, J=4Hz, 1H); 6.80(dd, J=4,8Hz, 1H); 5.02 (s, 2H); 3.70 (s, 3H); 3.18 (m, 1H); 2.83 (m,1H); 2.30 (m, 2H); 2.03 (m, 2H); 1.70 (m, 1H); 1.50 (m, 1H); 1.25 (s,3H); 1.10 (m, 1H) and 1.02 (s, 3H).

EXAMPLE 21 ##STR33##

To a solution of 5.3 g (11.1 mmol) of the compound of Example 20 in 90ml of a 1:2 AcOH/EtOH mixture, was added 10.0 g (153 mmol) of zinc dust.The mixture was reacted for 5 minutes at 80° C. and then cooled to roomtemperature, filtered and concentrated in vacuo to provide a solid. Thissolid was slurried in CH₂ Cl₂ and filtered. The filtrate was dried invacuo to provide a solid which was diluted with 100 ml of hot CHCl₃ andfiltered into 700 ml of hexane. The compound was then crystallized fromthis solution.

Yield: 3.31 g (99%).

¹ H NMR (300MHz, CDCl₃):δ7.82 (d, J=8HZ, 1H): 6.80 (d, J=4HZ, 1H); 6.70(dd, J=4,8Hz, 1H); 3.68 (s, 3H); 3.15 (m, 1H); 2.82 (m, 1H); 2.26 (m,2H); 2.03 (m, 2H); 1.67 (m, 1H); 1.50 (m, 1H); 1.20 (s, 3H); 1.17 (m,1H) and 1.08 (s, 3H).

MS: m/2 302 (M+).

EXAMPLE 22 ##STR34##

The compound was prepared substantially in accordance with the proceduredetailed in Example 15, using 440 mg (1.46 mmol) of the compound ofExample 21, 0.645 ml (3.7 mmol) of diisopropylethylamine, 179 mg (1.46mmol) of 4-dimethylaminopyridine, 845 mg (3.7 mmol) of the compound ofPreparation 1, 0.365 ml (4.5 mmol) of pyridine and 0.300 (4.1 mmol) ofthionyl chloride in 45 ml of CH₂ Cl₂.

Yield: 380 mg (51%).

¹ H NMR (300MHz, CDCl₃):δ8.08 (d, J=8Hz, 1H); 7.10 (d, J=4Hz, 1H); 7.0(dd, J=4,8Hz, 1H); 4.08 (m, 2H); 3.71 (s, 3H); 3.22 (m, 1H); 2.95 (m,3H); 2.72 (m, 1H); 2.30 (m, 2H); 2.05 (m, 4H); 1.75 (m, 3H) 1.47 (s,9H); 1.26 (s, 3H); 1.16 (m, 1H) and 1.14 (s, 3H).

MS: m/e 513 (M+).

EXAMPLE 23 ##STR35##

The compound was prepared substantially in accordance with theprocedures detailed in Examples 16 and 17, using 160 mg (0.31 mmol) ofthe compound of Example 22, 0.1 ml (0.63 mmol) of triethylsilane, 2.0 mlof a 1:1 CF₃ COOH/CH₂ Cl₂ mixture and 20 μl (0.31 mmol) ofmethanesulfonic acid.

Yield: 153 mg (97%).

¹ H NMR (300MHz, CDCl₃) δ8.05 (m, 1H); 7.10 (m, 1H); 7.0 (m, 1H); 3.65(s, 3H); 3.18 (m, 3H); 2.95 (m, 2H); 2.65 (m, 3H); 2.27 (bs, 3H); 2.05(m, 5H); 1.75 (m, 3H); 1.50 (m, 1H); 1.23 (s, 3H); 1.18 (m, 1H) and 1.10(s, 3H).

EXAMPLE 24 ##STR36##

To a solution of 250 mg (0.83 mmol) of the compound from Example 21 in8.0 ml of tetrahydrofuran (THF), was added 85 μl (0.87 mmol) of3-pyridylcarbinol, 236 mg (0.9 mmol) of triphenylphosphine and 142 μl(0.9 mmol) of diethyl azodicarboxylate. The reaction mixture was heatedto 65° C. and reacted for 10 minutes, cooled to room temperature andconcentrated in vacuo to provide an oily residue which was triturated inEt₂ O and filtered. The filtrate was washed sequentially with H₂ O and a0.1N K₂ CO₃ solution, dried over Na₂ SO₄, filtered and concentrated invacuo.

Yield: 198 mg of a tan solid (61%).

¹ H NMR (300MHz, CDCl₃):δ8.70 (s, 1H); 8.60 (d, J=4Hz, 1H); 8.05 (d,J=8Hz, 1H); 7.78 (d, J=8Hz, 1H); 7.35 (m, 1H); 6.95 (d, J=4Hz, 1H); 6.90(dd, J=4.8Hz, 1H); 5.13 (s, 2H); 3.70 (s, 3H); 3.18 (m, 1H); 2.95 (m,1H); 2.30 (m, 2H); 2.04 (m, 2H); 1.70 (m, 1H); 1.53 (m, 1H); 1.25 (s,3H); 1.13 (m, 1H) and 1.10 (s, 3H).

MS: m/e 393 (M+).

EXAMPLE 25 ##STR37##

To a solution of 38 mg (0.097 mmol) of the compound from Example 24 in2.2 ml of a 1:1:0.2 CH₃ CN/Et₂ O/hexane mixture, was added 0.1 ml of aHCl/CH₃ CN solution (1.0 ml of concentrated HCl in 11.0 ml of CH₃ CN)which resulted in the formation of a precipitate which was isolated byfiltration.

Yield: 40 mg (96%).

¹ H NMR (300MHz, CDCl₃): δ8.80 (bs, 1H); 8.65 (s, 1H); 8.55 (d, J=4Hz,1H); 7.98 (d, J=8HZ, 1H); 7.72 (d, J=8Hz, 1H); 7.30 (m, 1H); 6.90 (d,J=4Hz, 1H); 6.83 (dd, J=4,8Hz, 1H); 5.10 (s, 2H); 3.68 (s, 3H); 3.16 (m,1H); 2.91 (m, 1H); 2.27 (m, 2H); 2.0 (m, 2H); 1.68 (m, 1H); 1.50 (m,1H); 1.23 (s, 3H); 1.10 (m, 1H) and 1.03 (s, 3H).

MS: m/e 393 (M+-HCl).

EXAMPLE 26 ##STR38##

The compounds were prepared substantially in accordance with theprocedure detailed in Example 24, using 300 mg (0.992 mmol) of thecompound of Example 21, 214 mg (0.992 mmol) of the compound ofPreparation 2, 275 mg (1.05 mmol) of triphenylphosphine and 0.165 ml(1.05 mmol) of diethylazodicarboxylate in 9.0 ml of THF. The crudematerial was purified using radial chromatography (2000 micron plate,eluent of 5% EtOAc in CH₂ Cl₂).

Yield: 477 mg (96%).

¹ H NMR (300MHz, CDCl₃):δ8.01 (d, J=8Hz, 1H); 6.84 (d, J=4Hz, 1H); 6.78(dd, J=4,8Hz, 1H); 3.85 (m, 3H); 3.70 (s, 3H); 3.17 (m, 1H); 2.92 (m,2H); 2.30 (m, 2H); 2.02 (m, 3H); 1.88 (m, 1H); 1.68 (m, 3H); 1.50 (m,4H); 1.46 (s, 9H); 1.26 (s, 3H); 1.13 (m, 1H) and 1.10 (s, 3H).

MS: m/e 499 (M+).

EXAMPLE 27 ##STR39##

The compounds were prepared substantially in accordance with theprocedures detailed in Examples 16 and 25, using 378 mg (0.76 mmol) ofthe compound of Example 26, 0.20 ml (1.26 mmol) of triethylsilane, 5.0ml of a 2:3 CH₂ Cl₂ /CF₃ COOH mixture and 0.714 ml of a HCl/CH₃ CNsolution (1.0 ml of concentrated HCl in 11.0 ml of CH₃ CN).

Yield: 287 mg (87%).

¹ H NMR (300MHz, CDCl₃):δ9.02 (m, 2H); 7.80 (d, J=8Hz, 1H); 6.95 (s,1H); 6.87 (d, J=8Hz, 1H); 3.97 (m, 2H); 3.60 (s, 3H) ; 3.22 (m, 1H) ;3.03 (m, 1H); 3.74 (m, 3H) ; 2.20 (m, 5H); 1.75 (m, 5H); 1.35 (m, 2H);1.18 (s, 3H); 1.13 (m, 1H) and 1.0 (s, 3H).

MS: m/e 399 (M+-HCl).

EXAMPLE 28 ##STR40##

To a solution of 1.2 g (3.97 mmol) of the compound of Example 21 in 50ml of dioxane, was slowly added 210 mg (4.37 mmol) of a 50% dispersionof sodium hydride (NaH) in mineral oil, with stirring, followed by 663mg (3.97 mmol) of the compound from Preparation 3. The mixture washeated to 100° C. and reacted for 6 hours, then cooled and combined with5.0 ml of 1N sodium hydroxide (NaOH), followed by 200 ml of EtOAc. Theresultant layers were separated and the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.

Yield: 500 mg (32%).

¹ H NMR (300MHz, CDCl₃):δ7.98 (d, J=8Hz, 1H); 6.90 (d, J=4Hz, 1H); 6.83(dd, J=4,8Hz, 1H); 6.40 (bs, 1H); 5.6 (bs, 1H); 3.70 (s, 3H); 3.18 (m,1H); 2.95 (m, 1H); 2.28 (m, 2H); 2.02 (m, 2H); 1.70 (m, 1H); 1.61 (s,3H); 1.58 (s, 3H); 1.48 (m, 1H); 1.25 (s, 3H); 1.13 (m, 1H) and 1.10 (s,3H).

EXAMPLE 29 ##STR41##

To a solution of 480 mg (1.23 mmol) of the compound of Example 28 in amixture of 15.0 ml DMF and 2.0 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, was added 66 mg(1.36 mmol) of a 50% dispersion of NaH in mineral oil. The reactionmixture was refluxed for 5 minutes and then cooled to room temperature.To the mixture, was added 10 ml of a saturated NaHCO₃ solution followedby 100 ml of EtOAc. The resultant layers were separated and the organiclayer was sequentially washed with H₂ O and 0.2N HCl, dried over Na₂SO₄, filtered and concentrated in vacuo.

Yield: 380 mg of a tan solid (79%).

¹ H NMR (300MHz, CDCl₃):δ8.90 (bs, 1H); 8.02 (d, J=8Hz, 1H); 7.92 (d,J=4Hz, 1H); 7.32 (dd, J=4,8Hz, 1H); 3.70 (s, 3H); 3.22 (m, 1H); 2.97 (m,1H); 2.35 (m, 3H); 2.05 (m, 2H); 1.70 (m, 1H) ; 1.57 (s, 6H); 1.52 (m,1H) ; 1.25 (s, 3H); 1.15 (m, 1H) and 1.12 (s, 3H).

MS: m/e 387 (M+).

EXAMPLE 30 ##STR42##

To a solution of 100 mg (0.257 mmol) of the compound of Example 29 in5.0 ml of dioxane, was added 0.8 ml of 5N HCl.

The resultant mixture was heated to 100° C., reacted for 2 hours, cooledand then diluted with 50 ml of CH₂ Cl₂. The resultant layers wereseparated and the organic layer was washed with a saturated NaHCO₃solution dried over Na₂ SO₄, filtered and concentrated in vacuo toprovide a solid. This solid was purified using radial chromatography(1000 micron plate, eluent of 20% EtOAc in CH₂ Cl₂).

Yield: 46 mg (60%).

¹ H NMR (300MHz, CDCl₃):δ7.90 (d, J=8Hz, 1H); 6.55 (m, 2H); 4.12 (bs,2H); 3.70 (s, 3H); 3.15 (m, 1H); 2.90 (m, 1H); 2.27 (m, 2H); 2.02 (m,2H); 1.67 (m, 1H); 1.50 (m, 1H); 1.22 (s, 3H); 1.12 (m, 1H) and 1.08 (s,3H).

MS: m/e 301 (M+).

EXAMPLE 31 ##STR43##

To a solution of 25 mg (0.083 mmol) of the compound of Example 30 in 1.0ml CH₂ Cl₂, was slowly added 24 μl (0.172 mmol) of Et₃ N and 13 μl(0.168 mmol) of methanesulfonyl chloride. The reaction mixture wasdiluted with EtOAc and washed sequentially with 0.2N HCl and a saturatedNaHCO₃ solution, dried over Na₂ SO₄, filtered and concentrated in vacuo.

Yield: 31 mg of a white solid (82%).

¹ H NMR (300MHz, CDCl₃):δ8.13 (d, J=8Hz, 1H); 7.4 (s, 1H); 7.30 (d,J=8Hz, 1H); 3.73 (s, 3H); 3.40 (s, 6H); 3.25 (m, 1H); 3.03 (m, 1H); 2.35(m, 2H); 2.05 (m, 2H): 1.75 (m, 1H); 1.58 (m, 1H); 1.27 (s, 3H); 1.16(m, 1H) and 1.15 (s, 3H).

EXAMPLE 32 ##STR44##

The compound was prepared substantially in accordance with the proceduredetailed in Example 7, using 24 mg (0.053 mmol) of the compound ofExample 31, 4.6 mg (0.066 mmol) of hydroxylamine hydrochloride and 5.4mg (0.066 mmol) of NaoAc in 1.0 ml of EtOH. The crude material waspurified using radial chromatography (1000 micron plate, eluent of 5%EtOAc in CH₂ Cl₂).

Yield: 20 mg (80%).

¹ H NMR (300MHz, CDCl₃): δ8.0 (d, J=8Hz, 1H); 7.78 (s, 1H) 7.30 (d,J=4Hz, 1H); 7.18 (dd, J=4,8Hz, 1H); 3.72 (s, 3H); 3.42 (m, 1H); 3.40 (s,6H); 3.10 (m, 1H); 2.32 (m, 2H): 2.02 (m, 1H); 1.73 (m, 2H); 1.55 (m,1H); 1.33 (s, 3H); 1.13 (m, 1H) and 1.04 (s, 3H).

MS: m/e 472 (M+).

EXAMPLE 33 ##STR45##

To a solution of 1.5 g (4.96 mmol) of the compound of Example 21 and 278mg (4.96 mmol) of potassium hydroxide (KOH) in 50 ml of H₂ O, was added817 mg (6.6 mmol) of dimethylthiocarbamoyl chloride. The reactionmixture was stirred rapidly for 15 minutes. The reaction mixture wasdiluted with 100 ml of Et₂ O and the organic phase was separated, driedover Na₂ SO₄, filtered and concentrated in vacuo to provide an oilysolid which was triturated in MeOH and then isolated by filtration.

Yield: 1.45 g (75%).

¹ H NMR (300MHz, CDCl₃):δ8.10 (d, J=8Hz, 1H); 7.13 (d, J=4Hz, 1H); 7.0(dd, J=4,8Hz, 1H); 3.73 (s, 3H); 3.44 (s, 3H); 3.33 (s, 3H); 3.22 (m,1H); 2.98 (m, 1H); 2.30 (m, 2H); 2.05 (m, 2H); 1.62 (m, 2H); 1.28 (s,3H); 1.17 (m, 1H) and 1.14 (s, 3H).

MS: m/e 389 (M+).

EXAMPLE 34 ##STR46##

The compound was prepared by melting 300 mg (0.77 mmol) of the compoundof Example 33 in a flask under nitrogen (N₂). The liquified residue wascooled to provide 300 mg of a glassy solid (quantitative).

¹ H NMR (300MHz, CDCl₃): δ8.02 (d, J=8Hz, 1H); 7.58 (d, J=4Hz, 1H); 7.42(dd, J=4, 8Hz, 1H); 3.70 (s, 3H); 3.22 (m, 1H); 3.04 (m, 7H); 2.35 (m,2H); 2.05 (m, 2H); 1.70 (m, 1H); 1.57 (m, 1H); 1.27 (s, 3H); 1.16 (s,3H) and 1.14 (m, 1H).

MS: m/e 390 (M+).

EXAMPLE 35 ##STR47##

To a solution of 480 mg (1.23 mmol) of the compound of Example 34 in15.0 ml of MeOH, was added 689 mg (12.3 mmol) of KOH. The reactionmixture was refluxed for 20 minutes, cooled to room temperature, anddiluted with 80 ml of H₂ O and 100 ml of Et₂ O. The resulting layerswere separated and the aqueous layer was acidified with 4.0 ml of 5N HCland then combined with 100 ml of CH₂ Cl₂. The resultant layers wereseparated and the organic layer was dried over Na₂ SO₄, filtered andconcentrated in vacuo.

Yield: 370 mg of a tan solid (94%).

¹ H NMR (300MHz, CDCl₃):δ7.90 (d, J=8Hz, 1H); 7.24 (d, J=4Hz, 1H); 7.15(d, J=8Hz, 1H); 3.70 (s, 3H); 3.60 (s, 1H); 3.18 (m, 1H); 2.95 (m, 1H);2.32 (m, 2H); 2.02 (m, 2H); 1.72 (m, 1H); 1.50 (m, 1H); 1.25 (s, 3H);1.14 (m, 1H) and 1.10 (s, 3H).

MS: m/e 318 (M+).

EXAMPLE 36 ##STR48##

To a 0° C. solution of 320 mg (1.01 mmol) of the compound of Example 35in 20.0 ml of CH₃ CN was added 253 mg (2.5 mmol) of potassium nitrate(KNO₃) and 0.201 ml (2.5 mmol) of sulfuryl chloride. The reactionmixture was stirred for 30 minutes at 0° C., diluted with 100 ml of Et₂O and washed with 30 ml of H₂ O. The organic phase was separated, driedover Na₂ SO₄, filtered and concentrated in vacuo to provide 280 mg of acrude yellow solid. This solid was purified using radial chromatography(1000 micron plate, eluent of 2% EtOAc in CH₂ Cl₂).

Yield: 105 mg (27%).

¹ H NMR (300MHz, CDCl₃):δ8.23 (d, J=8Hz, 1H); 8.08 (d, J=4Hz, 1H); 7.93(dd, J=4,8Hz, 1H); 3.74 (s, 3H); 3.33 (m, 1H); 3.10 (m, 1H); 2.40 (m,2H); 2.03 (m, 2H); 1.75 (m, 1H); 1.55 (m, 1H); 1.28 (s, 3H); 1.18 (s,3H) and 1.16 (m, 1H).

MS: m/e 385 (M+). ##STR49##

The compound was isolated from the reaction mixture detailed in Example36A.

Yield: 135 mg.

¹ H NMR (300MHz, CDCl₃):δ8.02 (m, 3H); 5.8 (d, J=8Hz, 1H); 3.75 (s, 3H);2.35 (m, 3H); 1.85 (m, 3H); 1.53 (m, 1H); 1.50 (s, 3H) and 0.96 (s, 3H).

MS: m/e 418 (M+).

EXAMPLE 37 ##STR50##

To a solution of 100 mg (0.26 mmol) of the compound of Example 36A in1.0 ml of THF, was added 60 μl (0.84 mmol) of concentrated NH₄ OH. Thereaction mixture was diluted with 20.0 ml CH₂ Cl₂, washed with 10.0 mlH₂ O, dried over Na₂ SO₄, filtered and concentrated in vacuo.

Yield: 90 mg (95%).

¹ H NMR (300MHz, CDCl₃): δ8.13 (d, J=8Hz, 1H); 8.0 (d, J=4Hz, 1H); 7.80(dd, J=4,8Hz, 1H); 5.01 (s, 2H); 3.73 (s, 3H); 3.27 (m, 1H); 3.02 (m,1H); 2.38 (m, 2H); 2.02 (m, 2H); 1.73 (m, 1H); 1.54 (m, 1H); 1.27 (s,3H); 1.17 (m, 1H) and 1.13 (s, 3H).

EXAMPLE 38 ##STR51##

To a solution of 50 mg (0.157 mmol) of the compound of Example 35 in15.0 ml of EtOH, was added 100 mg of Rainey nickel catalyst. Thereaction mixture was shaken under hydrogen gas (60 psi) at roomtemperature for 3 hours and then filtered and concentrated in vacuo. Thecrude material was purified using radial chromatography (1000 micronplate, gradient eluent of 1-10% EtOAc in CH₂ Cl₂).

Yield: 15 mg (33%).

¹ H NMR (300MHz, CDCl₃): δ8.03 (d, J=8Hz, 1H); 7.54 (t, J=8Hz, 1H); 7.40(d, J=8Hz, 1H); 7.31 (d, J=8Hz, 1H); 3.72 (s, 3H); 3.22 (m, 1H); 3.0 (m,1H); 2.37 (m, 2H); 2.03 (m, 2H); 1.73 (m, 1H); 1.55 (m, 1H); 1.26 (s,3H); 1.14 (m, 1H) and 1.12 (s, 3H).

MS: m/e 286 (M+).

EXAMPLE 39 ##STR52##

To a solution of 200 mg (0.632 mmol) of the compound of Example 6 in 2.5ml of EtOH was added 43 μl (0.75 mmol) of ACOH, and 396 μl (5.2 mmol) of1,1-dimethylhydrazine. The reaction mixture was heated to 80° C. andreacted for 4 hours, concentrated in vacuo, diluted with Et₂ O, washedwith H₂ O, dried over Na₂ SO₄, filtered and then concentrated in vacuoto provide an oil. This oil was purified using radial chromatography(2000 micron plate, eluent of 8% EtOAc in CH₂ Cl₂)

Yield: 145 mg (64%).

¹ H NMR (300MHz, CDCl₃):δ8.13 (d, J=8Hz, 1H); 6.81 (d, J=4Hz, 1H); 6.74(dd, J=4,8Hz, 1H); 3.81 (s, 3H); 3.71 (s, 3H); 3.61 (m, 1H); 2.78 (m,1H); 2.60 (s, 6H); 2.28 (m, 2H); 1.72 (m, 2H); 1.47 (m, 1H); 1.32 (s,3H); 1.12 (m, 1H) and 1.06 (s, 3H).

MS: m/e 358 (M+).

Elemental Analysis for C₂₁ H₃₀ N₂ O₃ :

Calcd: C, 70.36; H, 8.44; N, 7.81;

Found: C, 70.30; H, 7.91; N, 8.00.

EXAMPLE 40 ##STR53##

To a solution of 98 mg (0.273 mmol) of the compound from Example 39 in2.0 ml of Et₂ O, was added 0.273 ml of a solution containing 1.0 ml ofconcentrated HCl in 11.0 ml of CH₃ CN. The reaction mixture was dilutedwith 10.0 ml of CH₃ CN and then concentrated in vacuo to provide an oilyresidue. This residue was triturated with 3.0 ml of Et₂ O and thenisolated by filtration.

Yield: 105 mg (97%).

¹ H NMR (300MHz, d₆ -DMSO):δ8.35 (bs, 1H); 8.10 (d, J=8Hz, 1H); 6.80 (d,J=4Hz, 1H); 6.71 (dd, J=4, 8Hz, 1H); 3.78 (s, 3H); 3.68 (s, 3H); 3.57(m, 1H); 2.74 (m, 1H); 2.58 (s, 6H); 2.26 (m, 2H); 1.70 (m, 2H); 1.45(m, 1H); 1.30 (s, 3H); 1.10 (m, 1H) and 1.02 (s, 3H).

MS: m/e 358 (M+-HCl).

Elemental Analysis for C₂₁ H₃₁ N₂ O₃ Cl:

Calc: C, 63.87; H, 7.91; N, 7.09; Cl, 8.98;

Found: C, 64.17; H, 8.07; N, 7.07; Cl, 9.08.

EXAMPLE 41 ##STR54##

To a solution of 2.0 g (6.32 mmol) of the compound from Example 6 in20.0 ml of EtOH, was added 12.0 ml (100 mmol) of1-amino-4-methylpiperazine, 2.8 g (50 mmol) of KOH. The mixture washeated to 80° C. for 2 hours, concentrated in vacuc, diluted with 250 mlof Et₂ O, and washed with 100 ml of H₂ O. The resultant layers wereseparated and the organic layer was dried over Na₂ SO₄, filtered andconcentrated in vacuo to provide a thick oil. This oil was purifiedusing radial chromatography (4000 micron plate, gradient eluent of 0-15%MeOH in EtOAc).

Yield: 2.29 g (88%).

¹ H NMR (300MHz, CDCl₃):δ8.13 (d, J=8Hz, 1H); 6.80 (d, J=4Hz, 1H); 6.72(dd, J=4,8Hz, 1H); 3.80 (s, 3H); 3.70 (s, 3H); 3.66 (m, 1H); 2.95 (m,2H); 2.80 (m, 2H); 2.70 (m, 1H); 2.60 (m, 4H); 2.35 (s, 3H); 2.26 (m,2H); 1.95 (m, 1H); 1.70 (m, 2H); 1.45 (m, 1H); 1.30 (s, 3H); 1.10 (m,1H) and 1.03 (s, 3H).

EXAMPLE 42 ##STR55##

The compound was prepared substantially in accordance with the proceduredetailed in Example 40, using 2.29 g (5.54 mmol) of the compound ofExample 41, and 5.54 ml of a solution consisting of 1.0 ml concentratedHCl and 11.0 ml of CH₃ CN.

Yield: 2.31 g (93%).

¹ H NMR (300MHz, d₆ -DMSO):δ10.5 (bs, 1H); 8.02 (d, J=8Hz, 1H); 6.88 (d,J=4Hz, 1H); 6.80 (dd, J=4,8Hz, 1H); 3.78 (s, 3H) ; 3.64 (s, 3H) ; 3.50(m, 1H) ; 3.33 (m, 4H) ; 3.03 (m, 4H) 2.63 (m, 1H); 2.77 (s, 3H); 2.30(m, 1H); 2.10 (m, 1H); 1.84 (m, 1H); 1.68 (m, 1H); 1.58 (m, 1H); 1.31(m, 1H); 1.20 (s, 3H); 1.10 (m, 1H) and 0.93 (s, 3H).

MS: m/e 413 (M+-HCl).

Elemental Analysis for C₂₄ H₃₆ N₃ O₃ Cl:

Calcd: C, 64.05; H, 8.06; N, 9.34; Cl, 7.21;

Found: C, 63.85; H, 7.98; N, 9.50; Cl, 7.67.

EXAMPLE 43 ##STR56##

To a solution of 330 mg (1.04 mmol) of the compound from Example 6 in4.0 ml of EtOH was added 100 mg (1.2 mmol) of methoxyamine hydrochlorideand 98 mg (1.2 mmol) of NaOAc. The reaction mixture was stirred at roomtemperature for 67 hours, heated to 80° C. and reacted for approximately3 hours and then concentrated in vacuo. The crude material was purifiedusing radial chromatography (2000 micron plate, eluent of 3% EtOAc inCH₂ Cl₂) to provide an oil which was dissolved in MeOH andrecrystallized at 0° C.

Yield: 43 mg (12%).

¹ H NMR (300MHz, CDCl₃): δ7.95 (d, J=8Hz, 1H); 6.83 (d, J=4Hz, 1H); 6.75(dd, J=4,8Hz, 1H); 4.0 (s, 3H); 3.82 (s, 3H); 3.72 (s, 3H); 3.32 (m,1H); 2.97 (m, 1H); 2.28 (m, 2H); 1.98 (m, 1H); 1.68 (m, 2H); 1.52 (m,1H); 1.25 (s, 3H); 1.10 (m, 1H) and 0.98 (s, 3H).

MS: m/e 345 (M+).

EXAMPLE 44 ##STR57##

To a solution of 175 mg (0.528 mmol) of the compound from Example 7 in3.0 ml of dioxane, was added 235 mg (1.70 mmol) of K₂ CO₃ and 112 mg(0.687 mmol) of 3-picolyl chloride hydrochloride. The reaction mixturewas heated to 100° C., reacted for 15 minutes and then concentrated invacuo to provide a tan residue. This residue was dissolved in 75.0 ml ofEtOAc, washed with a saturated NaHCO₃ solution, dried over Na₂ SO₄,filtered and then concentrated in vacuo to provide 180 mg of crudematerial which was purified using radial chromatography (2000 micronplate, gradient eluent of 5-20% EtOAc in CH₂ Cl₂).

Yield: 90 mg (40%).

¹ H NMR (300MHz, CDCl₃):δ8.70 (m, 1H); 8.55 (m, 1H); 7.9 (d, J=8Hz, 1H);7.77 (m, 1H); 7.30 (m, 1H); 6.80 (d, J=4Hz, 1H); 6.72 (dd, J=4,8Hz, 1H);5.22 (s, 2H); 3.80 (s, 3H); 3.70 (s, 3H); 3.37 (m, 1H); 3.02 (m, 1H);2.25 (m, 2H); 1.95 (m, 1H); 1.67 (m, 2H); 1.50 (m, 1H); 1.27 (s, 3H);1.10 (m, 1H) and 0.97 (s, 3H).

EXAMPLE 45 ##STR58##

To a solution of 500 mg (1.58 mmol) of the compound from Example 6 in5.0 ml of MeOH was added 101 mg (1.6 mmol) of sodium cyanoborohydrideand a trace (a trace) of methyl orange. A 2N HCl methanolic solution wasadded dropwise to maintain the red color of the reaction. Afterapproximately 15 minutes, the color stabilized (red) and the reactionwas stirred for 45 minutes longer. The reaction mixture was concentratedin vacuo to provide an orange residue. The residue was dissolved in Et₂O and washed with brine, dried over Na₂ SO₄, filtered and concentratedin vacuo to provide an oil which solidified on standing. The solid waspurified using radial chromatography (4000 micron plate, eluent of 5%EtOAc in CH₂ Cl₂).

Yield: 226 mg (45%).

¹ H NMR (300MHz, CDCl₃):δ7.50 (d, J=8Hz, 1H); 6.77 (m, 2H); 4.68 (m,1H); 3.80 (s, 3H); 3.62 (s, 3H); 2.55 (m, 1H); 2.22 (m, 2H); 1.90 (m,3H); 1.58 (m, 2H); 1.35 (m, 1H); 1.27 (s, 3H); 1.03 (m, 1H) and 1.0 (s,3H).

MS: m/e 318 (M+).

EXAMPLE 46 ##STR59##

To a solution of 1.0 g (3.16 mmol) of the compound from Example 6 in15.0 ml of MeOH, was added 1.0 g crushed and activated 4.0 Å molecularsieves, 2.46 g (32 mmol) of ammonium acetate and 201 mg (3.2 mmol) ofsodium cyanoborohydride. The reaction was stirred at room temperaturefor 1 hour and then quenched with 30.0 ml of H₂ O. The desired compoundswere extracted with 100 ml of Et₂ O, washed with a saturated NaHCO₃solution, dried over Na₂ SO₄, filtered and then concentrated in vacuo toprovide a yellow residue. This residue was purified using flashchromatography (SiO₂, gradient eluent of 0-5% EtOAc in CH₂ Cl₂).

Yield: 290 mg (29%).

¹ NMR (300MHz, CDCl₃):δ7.45 (d, J=8Hz, 1H); 6.78 (m, 2H); 3.85 (m, 1H);3.78 (s, 3H); 3.67 (s, 3H); 2.40 (m, 1H); 2.22 (m, 2H); 1.95 (m, 2H);1.78 (m, 1H); 1.58 (m, 3H); 1.40 (m, 1H); 1.27 (s, 3H); 1.10 (m, 1H) and1.05 (s, 3H).

EXAMPLE 47 ##STR60##

To a solution of 20 mg (0.063 mmol) of the compound from Example 46 in3.0 ml of a 2:1 Et₂ O/hexane mixture, was added 63 μl of a solutionconsisting of 1.0 ml of concentrated HCl in 11.0 ml of CH₃ CN. Theresultant precipitate was filtered, washed with 3.0 ml of a 1:1 Et₂O/hexane mixture and dried in vacuo.

Yield: 21 mg (95%).

¹ H NMR (300MHz, d₆ -DMSO):δ8.42 (m, 3H); 7.50 (d, J=8Hz, 1H); 6.82 (m,2H); 4.35 (m, 1H); 3.70 (s, 3H); 3.58 (s, 3H); 2.50 (m, 1H); 2.20 (m,2H); 1.87 (m, 2H); 1.58 (m, 2H); 1.25 (m, 1H); 1.20 (s, 3H); 1.10 (m,1H) and 1.0 (s, 3H).

MS: m/e 317 (M+).

EXAMPLE 48 ##STR61##

To a solution of 1.0 g (3.16 mmol) of the compound from Example 6 in15.0 ml of CH₂ Cl₂, was added 0.44 ml (3.8 mmol) of 2,6-lutidine and0.80 ml (3.5 mmol) of t-butyldimethylsilyl trifluoromethanesulfonate.The reaction mixture was stirred at room temperature for 1 hour, dilutedwith Et₂ O and washed sequentially with H₂ O and a saturated NaHCO₃solution, dried over Na₂ SO₄, filtered and concentrated in vacuo.

Yield: 1.36 g (quantitative).

¹ H NMR (300MHz, CDCl₃): δ7.42 (d, J=8Hz, 1H); 6.78 (d, J=4Hz, 1H); 6.72(dd, J=4,8Hz, 1H); 5.55 (d, J=4Hz, 1H); 3.80 (s, 3H); 3.68 (s, 3H); 2.42(d, J=4Hz, 1H); 2.30 (m, 1H); 2.15 (m, 1H); 1.95 (m, 1H); 1.65 (m, 2H);1.27 (s, 3H); 1.10 (m, 1H); 1.03 (s, 9H); 0.90 (s, 3H); 0.28 (s, 3H) and0.18 (s, 3H).

EXAMPLE 49 ##STR62##

To a solution of 1.36 g (3.16 mmol) of the compound from Example 48 in10.0 ml of THF, was added 1.6 ml of a 1M bromine in AcOH solution. Thereaction mixture was diluted with Et₂ O, washed with a saturated NaHCO₃solution, dried over Na₂ SO₄, filtered and then concentrated in vacuo toprovide a yellow solid. This solid was dissolved in 10.0 ml of MeOH,cooled to 0° C. and reacted for 18 hours. The resultant white crystalswere filtered and dried in vacuo.

Yield: 935 mg (75%).

¹ H NMR (300MHz, CDCl₃):δ7.82 (d, J=8Hz, 1H); 6.88 (dd, J=4,8Hz, 1H);6.83 (d, J=8Hz, 1H); 5.82 (d, J=6Hz, 1H); 3.86 (s, 3H); 3.73 (s, 3H);2.52 (d, J=6Hz, 1H); 2.37 (m, 1H); 2.17 (m, 1H); 1.92 (m, 1H); 1.78 (m,2H); 1.57 (s, 3H); 1.22 (m, 1H) and 0.87 (s, 3H).

EXAMPLE 50 ##STR63##

To a solution of 910 mg (2.30 mmol) of the compound from Example 49 in10.0 ml of MeOH, was added 11.2 ml (5.6 mmol) of a 0.5M sodium methoxide(NaOMe) in MeOH solution. The reaction mixture was heated to 65° C. for5 hours and then concentrated in vacuo to provide a residue which wasdissolved in a 2:1 Et₂ O/H₂ O mixture. The resulting layers wereseparated and the organic layer was dried over Na₂ SO₄, filtered andconcentrated in vacuo.

Yield: 705 mg (98%). ¹ H NMR (300 MHz, CDCl₃): δ 8.15 (d, J=8 Hz, 1H);6.93 (m, 2H); 6.57 (s, 1H); 3.87 (s, 3H); 3.63 (s, 3H); 2.52 (m, 1H);2.30 (m, 1H); 2.13 (m, 1H); 1.70 (m, 1H); 1.50 (m, 1H); 1.47 (s, 3H);1.31 (s, 3H) and 1.24 (m, 1H). MS: m/e 314 (M+).

Elemental Analysis for C₁₉ H₂₂ O₄ : Calc: C, 72.59; H, 7.05; Found: C,72.72; H, 7.13.

EXAMPLE 51 ##STR64##

To a solution of 100 mg (0.318 mmol) of the compound from Example 50 in5.0 ml of EtOH, was added 1.47 g (21.2 mmol) of hydroxylaminehydrochloride and 1.74 g (21.2 mmol) of NaOAc. The reaction mixture washeated to 78° C. and reacted for 18 hours and then concentrated in vacuoto provide a residue which was dissolved in a 2:1 EtOAc/H₂ O mixture.The resultant layers were separated and the organic layer was dried overNa₂ SO₄, filtered and concentrated in vacuo to provide a yellow solidwhich was purified using radial chromatography (1000 micron plate(eluent of 1% MeOH in CH₂ Cl₂).

Yield: 87 mg (83%). ¹ H NMR (300 MHz, CDCl₃): δ 8.30 (bs, 1H); 7.95 (d,J=8 Hz, 1H); 7.30 (s, 1H); 6.85 (m, 2H); 3.82 (s, 3H); 3.62 (s, 3H):2.45 (m, 1H); 2.25 (m, 1H); 2.10 (m, 1H); 1.65 (m, 1H); 1.57 (m, 1H);1.53 (s, 3H); 1.27 (s, 3H) and 1.22 (m, 1H) MS: m/e 329 (M+).

Elemental Analysis for C₁₉ H₂₃ NO₄ : Calc: C, 69.28; H, 7.04; N, 4.25;Found: C, 69.29; H, 7.23; N, 4.23.

EXAMPLE 52 ##STR65##

To a solution of 150 mg (0.48 mmol) of the compound from Example 50 in2.0 ml of EtOH, was added 28 μl (0.48 mmol) of AcOH and 555 μl (11.4mmol) of hydrazine. The reaction mixture was heated to 80° C. for 7hours, concentrated in vacuo to provide a residue. This residue wasdiluted with 100 ml of Et₂ O, washed with a saturated NaHCO₃ solution,dried over Na₂ SO₄, filtered and concentrated in vacuo to provide anoily residue. This residue was dissolved in 5.0 ml of hot hexane andcooled to 0° C. for 16 hours.

Yield: 135 mg (85%). ¹ H NMR (300 MHz, CDCl₃ ): δ 8.0 (d. J=8 Hz, 1H);6.80 (m, 3H); 5.40 (s, 2H); 3.80 (s, 3H); 3.60 (s, 3H); 2.45 (m, 1H);2.27 (m, 1H); 2.08 (m, 1H); 1.70 (m, 1H); 1.55 (m, 1H); 1.27 (s, 3H) and1.22 (m, 1H). MS: m/e 328 (M+).

EXAMPLE 53 ##STR66##

To a cold (0° C.) solution of 595 mg (1.87 mmol) of the compound fromExample 45 in 3.5 ml of CH₃ CN, was added a mixture containing 2.0 mlCF₃ COOH/0.1 ml CH₃ CN/0.2 ml H₂ O. The reaction mixture was warmed toroom temperature, stirred for 30 minutes and then diluted with 50.0 mlof EtOAc. The resultant layers were separated and the organic layer waswashed sequentially with H₂ O and a saturated NaHCO₃ solution, driedover Na₂ SO₄, filtered and concentrated in vacuo.

Yield: 494 mg (88%). ¹ H NMR (300 MHz, CDCl₃): δ 7.0 (d, J=8 Hz, 1H);6.80 (d, J=4 Hz, 1H); 6.67 (dd, J=4,8 Hz, 1H); 6.40 (m, 2H); 3.80 (s,3H); 3.70 (s, 3H); 2.35 (m, 2H); 2.20 (m, 1H); 1.95 (m, 1H); 1.65 (m,2H); 1.30 (s, 3H); 1.13 (m, 1H) and 0.87 (s, 3H)

EXAMPLE 54 ##STR67##

To a solution of 1.0 g (3.31 mmol) of the compound from Example 1A in10.0 ml of THF, was added 1.0 g (6.4 mmol) of benzeneselenol, 302 mg(6.29 mmol) of a 50% dispersion of NaH in mineral oil and 84 mg (0.32mmol) of 18-crown-6 ether. The reaction mixture was refluxed for 15hours, cooled to room temperature and diluted with 100 ml of Et₂ O and20 ml of 1N HCl. The resultant layers were separated and the organiclayer was dried over Na₂ SO₄, filtered and concentrated in vacuo. Thecrude material was purified using flash chromatography (SiO₂, eluent of25% EtOAc in hexane) to provide a solid which was recrystallized fromEt₂ O/hexane.

Yield: 731 mg (77%) ¹ H NMR (300 MHz, CD₃ O): δ 6.9 (d, J=8 Hz, 1H);6.75 (d, J=4 Hz, 1H); 6.60 (dd, J=4.8 Hz, 1H); 3.70 (s, 3H); 2.70 (m,2H); 2.20 (m, 3H); 2.20 (m, 2H); 1.53 (m, 2H); 1.33 (m, 1H); 1.27 (s,3H); 1.10 (s, 3H) and 1.07 (m, 1H). MS: m/e 288 (M+).

EXAMPLE 55 ##STR68##

To a solution of 360 mg (1.25 mmol) of the compound from Example 54 in25.0 ml of toluene, was added 0.545 ml (6.25 mmol) of oxalyl chloride in25 μl of DMF. The reaction mixture was stirred at room temperature withgas evolution for 30 minutes, heated briefly (2 minutes) to reflux andthen concentrated in vacuo.

Yield: 381 mg crystals (99%). ¹ H NMR (300 MHz, CDCl₃ ): δ 6.98 (d, J=8Hz, 1H); 6.82 (d, J=4 Hz, 1H); 6.68 (dd, J=4,8 Hz, 1H); 3.80 (s, 3H);2.80 (m, 2H); 2.25 (m, 3H); 2.05 (m, 2H); 1.65 (m, 2H); 1.42 (m, 1H);1.40 (s, 3H); 1.25 (s, 3H) and 1.20 (m, 1H).

EXAMPLE 56 ##STR69##

To a solution of 100 mg (0.33 mmol) of the compound from Example 55 in2.0 ml of CH₂ Cl₂, were added 43 μl (0.358 mmol) of2-(2-aminoethyl)pyridine, 50 μl (0.36 mmol) of Et₃ N and 5 mg (0.036mmol) of 4-dimethylaminopyridine in 4.0 ml of CH₂ Cl₂. The reactionmixture was diluted with CH₂ Cl₂, washed with H₂ O, dried over Na₂ SO₄,filtered and concentrated in vacuo to provide a tan solid. This solidwas dissolved in 3.0 ml of CH₃ CN and treated with 0.36 ml of a solutionof 1.0 ml of concentrated HCl in 11.0 ml of CH₃ CN.

Yield: 120 mg (78%). ¹ H NMR (300 MHz, d₆ -DMSO): δ 8.75 (d, J=6 Hz,1H); 8.40 (t, J=6 Hz, 1H); 7.80 (m, 2H); 7.40 (m, 1H); 6.85 (d, J=8 Hz,1H); 6.70 (d, J=4 Hz, 1H); 6.60 (dd, J=4, 8 Hz, 1H); 3.60 (s, 3H); 3.55(m, 2H); 3.19 (m, 2H); 2.68 (m, 1H); 2.55 (m, 1H); 2.10 (m, 3H); 1.78(m, 2H); 1.43 (m, 1H); 1.30 (m, 1H); 1.17 (m, 1H); 1.02 (s, 3H); 0.99(m, 1H) and 0.80 (s, 3H). MS: m/e 392 (M+--HCl).

EXAMPLE 57 ##STR70##

To a solution of NaOme (prepared in situ from 2.6 g of sodium and 400 mlof anhydrous MeOH (0.108 mol), under N₂), was added 15.0 g (0.035 mol)of 70% abietic acid. After stirring the mixture for 10 minutes, 14.0 ml(0.22 mol) of iodomethane was added and the mixture was refluxed for 24hours, cooled and concentrated in vacuo to provide a residue. Thisresidue was dissolved in 500 ml of EtOAc, washed sequentially with 500ml of a saturated NaHCO₃ solution and a saturated sodium chloridesolution (NaCl), dried over Na₂ SO₄, filtered and concentrated in vacuo.The crude material was purified using flash chromatography (eluent of 2%EtOAc in hexanes).

Yield: 10.0 g of a dark yellow oil (90.4%). IR(CHCl₃): 2952, 1718 and1251 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃ ): δ 5.78 (s, 1H); 5.38 (brs, 1H);3.66 (s, 3H); 2.17-2.30 (m, 3H); 1.68-2.16 (m, 8H); 1.50-1.65 (m, 2H);1.26 (s, 3H); 1.24 (m, 2H); 1.02 (d, J=2.6 Hz, 3H); 1.00 (d, J=2.6 Hz,3H) and 0.83 (s, 3H). MS(FD): m/e 316(M+).

Elemental Analysis for C₂₁ H₃₂ O₂ : Calcd: C, 79.70; H, 10.19; Found: C,79.49; H, 9.94.

EXAMPLE 58 ##STR71##

To a mixture of 5.0 g (15.8 mmol) of the compound in Example 57 in 100ml of acetic anhydride, was added 2.5 g (22.5 mmol) of selenium (IV)oxide, under N₂. The reaction mixture was warmed to 70° C., stirred for16 hours, cooled, filtered and then diluted to 500 ml with CH₂ Cl₂. Theresulting layers were separated and the organic layer was washed with500 ml of NaCl, dried over Na₂ SO₄, filtered and then concentrated invacuo to provide a dark yellow solid. This solid was purified usingflash chromatography (eluent of 5% EtOAc in hexanes) to provide twomajor fractions.

The first fraction was concentrated to provide 537 mg of an oil. Thisoil was hydrogenated with 135 mg of 5% Pd/C in 25 ml of MeOH (8 hours,room temperature, 6.0 psi). The reaction mixture was filtered and thefiltrate concentrated in vacuo. The crude material was purified usingflash chromatography (eluent of 2% EtOAc in hexanes) to provide thecompound of Example 59 (400 mg of a clear oil (75%) m.p. 50° C.). Thesecond fraction was concentrated in vacuc to provide the compound.

Yield: 2.8 g of a light yellow solid (47%). m.p. 165-167° C. IR (KBr):2956, 1722 and 1251 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.23 (m, 2H); 7.04(d, J=1.8 Hz, 1H); 5.90 (m, 1H); 3.64 (s, 3H); 2.86 (m, 1H); 2.60 (dd,J=1.5,11.0 Hz, 1H); 2.31 (d, J=12.1 Hz, 1H); 2.08 (s, 3H); 2.07 (m, 1H);1.60-1.80 (m, 6H); 1.26 (s, 3H); 1.24 (s, 3H); 1.22 (s, 3H) and 1.19 (s,3H). MS(FD): m/e 372(M+).

Elemental Analysis for C₂₃ H₃₂ O₄ : Calcd: C, 74.16; H, 8.66; Found: C,74.44; H, 8.71.

EXAMPLE 59 ##STR72##

To a mixture of 23.6 g (0.063 mmol) of the compound in Example 58 in1500 ml of MeOH, was added 5.8 g of 10% Pd/C and 5.8 g (0.030 mmol) ofp-toluenesulfonic acid monohydrate. The reaction mixture was reacted for16 hours at room temperature, 60 psi, filtered and then concentrated invacuo to provide a residue. This residue was dissolved in 700 ml ofEtOAc, washed sequentially with 700 ml of saturated NaHCO₃ and NaClsolutions, dried over Na₂ SO₄, filtered and then concentrated in vacuo.

Yield: 19.3 g (97.5%) of an oil. IR (CHCl₃), 2955, 1718 and 1254 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.16 (d, J=8 Hz, 1H); 7.00 (d, J=8 Hz, 1H);6.88 (s, 1H); 3.66 (s, 3H); 2.80-2.90 (m, 3H); 2.23-2.32 (m, 2H);1.35-1.90 (m, 7H); 1.28 (s, 3H); 1.24 (s, 3H) and 1.21 (s, 6H). MS(FD):m/e 314(M+).

Elemental Analysis for C₂₁ H₃₀ O₂ : Calcd: C, 80.21; H, 9.62 Found: C,80.34; H, 9.73

EXAMPLE 60 ##STR73##

To a suspension of 185 mg (0.50 mmol) of the compound of Example 58 in10 ml of MeOH, was added 5 ml (0.50 mmol) of 0.1N NaOH. The reactionmixture was refluxed for 2 hours, cooled and partitioned between 50 mlof EtOAc and 50 ml of 0.2N HCl. The resulting layers were separated andthe organic layer was washed with 50 ml of a saturated NaCl solution,dried over Na₂ SO₄, filtered and then concentrated in vacuo to provide ayellow oil which was purified using flash chromatography (eluent of 10%EtOAc in hexanes).

Yield: 158 mg of a clear oil (96%). m.p. 105-107° C. IR (KBr): 2957,3500 and 1719 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.20 (m, 3H); 4.75 (t,J=4.8 Hz, 1H); 3.69 (s, 3H); 2.88 (m, 1H); 2.50 (dd, J=1.8,13.2 Hz, 1H);2.30 (brd, J=12.1 Hz, 1H); 2.06-2.17 (m, 1H); 1.98 (d, J=7.0 Hz, 1H);1.69-1.84 (m, 4H); 1.55 (m, 2H); 1.29 (s, 3H); 1.25 (s, 3H); 1.23 (s,3H) and 1.17 (s, 3H). MS(FD): m/e 330(M+).

EXAMPLE 61 ##STR74##

To a solution of 112 mg (0.30 mmol) of the titled compound of Example 60in 4 ml of glacial AcOH and 1 ml of H₂ O, was added 10 mg (1.0 mmol) ofchromium trioxide. The resultant mixture was stirred at room temperaturefor 1 hour and then partitioned between 50 ml of EtOAc and 50 ml of asaturated NaCl solution. The resultant layers were separated and theorganic layer was dried over Na₂ SO₄, filtered and then concentrated invacuo to provide a dark oil. This oil was purified using flashchromatography (eluent of 5% EtOAc in hexanes) to provide an oil whichsolidified on standing.

Yield: 100 mg (90%). IR (CHCl₃): 2965, 1722, 1675 and 1253 cm⁻¹. ¹ H NMR300 MHz, CDCl₃): δ 7.88 (d, J=1.8 Hz, 1H); 7.42 (dd, J=1.8,8.1 Hz, 1H);7.30 (d, J=8.1 Hz, 1H); 3.66 (s, 3H); 2.86-298 (m, 1H); 2.66-2.76 (m,2H); 2.28-2.40 (m, 2H); 1.60-1.90 (m, 5H); 1.35 (s, 3H); 1.26 (s, 6H)and 1.24 (s, 3H). MS(FD): m/e 329(M+).

Elemental Analysis for C₂₁ H₂₈ O₃ : Calcd: C, 76.79; H, 8.59; Found: C,76.52; H, 8.53.

EXAMPLE 62 ##STR75##

A mixture containing 118 mg (0.36 mmol) of the compound of Example 61,40 mg (0.58 mmol) of hydroxylamine hydrochloride, 40 mg (0.48 mmol) ofNaHCO₃, 1 drop of glacial AcOH, 1.0 ml of H₂ O and 15 ml of MeOH waswith a Dean-Stark trap for approximately 5 hours. The reaction mixturewas concentrated in vacuo to provide a residue. This residue waspartitioned between H₂ O and CH₂ Cl₂ and the organic layer was driedover Na₂ SO₄, filtered and concentrated in vacuo. The crude material waspurified using flash chromatography.

Yield: 120 mg (97%). IR(CHCl₃): 3582, 2962, 1721 and 1261 cm⁻¹. ¹ H NMR(300 MHz, CDCl₃ ): δ 7.71 (s, 1H); 7.43 (s, 1H); 7.21 (s, 2H); 3.66 (s,3H); 2.85-2.95 (m,1H); 2.67 (m, 2H); 2.26-237 (m, 2H); 1.75 (m, 5H);1.38 (s, 3H); 1.26 (s, 3H); 1.24 (s, 3H); 1.13 (s, 3H); MS(FD) m/e343(M+).

EXAMPLE 63 ##STR76##

A mixture of 500 mg (1.59 mmol) of the compound of Example 59, 1.0 g(17.8 mmol) of KOH and 20 ml of n-butyl alcohol was refluxed for 16hours, under N₂. After cooling, the mixture was acidified with 5N HCland concentrated in vacuo to provide a residue. This residue wassuspended in 50 ml of H₂ O and filtered. The resulting solid wasdissolved in 50 ml of MeOH, filtered and the filtrate was concentratedin vacuo.

Yield: 330 mg of a foam (69%). m.p. 143-145° C. IR (KBr): 2958, 1695 and1279 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.25 (d, J=3 Hz, 1H); 7.17 (d,J=8 Hz, 1H); 7.00 (dd, J=3.9 Hz, 1H); 6.89 (brs, 1H); 2.80-3.00 (m, 3H);2.20-2.40 (m, 2H); 1.65-1.96 (m, 5H); 1.43-1.60 (m, 2H); 1.29 (s, 3H);1.24 (s, 3H); 1.22 (S, 3H); 1.21 (S, 3H); MS(FD) m/e 301(m+).

Elemental Analysis for C₂₀ H₂₈ O₂ ·0.5H₂ O: Calcd: C, 79.01; H, 9.47;Found: C, 79.19; H, 9.52.

EXAMPLE 64 ##STR77##

To a cold (0° C.) solution of 8.0 g (25.0 mmol) of the compound ofExample 59 in 50 ml of acetic anhydride and 38 ml of AcOH, was added11.0 g (0.11 mmol) of chromium trioxide slowly, under N₂. The reactionmixture was partitioned between EtOAc and brine and the organic layerwas dried over Na₂ SO₄, filtered and concentrated to provide a yellowoil which was purified using flash chromatography (SiO₂, eluent of 10%EtOAc in hexanes) to provide a solid which was filtered with the aid ofhexanes.

Yield: 2.5 g (30.5%). m.p. 144-145° C. IR (KBr): 2951, 1725 and 1680cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 8.55 (d, J=2 Hz, 1H); 8.17 (dd, J=2.8Hz, 1H); 7.50 (d, J=8 Hz, 1H); 3.66 (s, 3H); 2.75 (m, 2H); 2.64 (s, 3H);2.37-2.50 (m, 2H); 1.60-1.90 (m, 5H); 1.37 (s, 3H) and 1.29 (s, 3H).MS(FD): m/e 328 (M+).

Elemental Analysis for C₂₀ H₂₄ O₄ : Calcd: C, 73.15; H, 7.37; Found: C,72.86; H, 7.42.

EXAMPLE 65 ##STR78##

The compound was isolated from the reaction mixture described in Example64.

Yield: 4.2 g of a white solid (43.5%). m.p. 130-133° C. IR (KBr): 2934.1734, 1720 and 1680 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃ ): δ 7.98 (d, J=2 Hz,1H); 7.54 (dd, J=2.8 Hz, 1H); 7.33 (d, J=8 Hz, 1H); 3.66 (s, 3H); 2.75(m, 2H); 2.30-2.42 (m, 2H); 2.2 (m, 1H); 2.04 (s, 3H); 2.00-2.10 (m,1H); 1.70-1.90 (m, 3H); 1.76 (s, 6H); 1.35 (s, 3H) and 1.26 (s, 3H).MS(FD): m/e 386 (M+).

Elemental Analysis for C₂₃ H₃₀ O₅ : Calcd: C, 71.48; H, 7.82; Found: C,71.75; H, 8.03.

EXAMPLE 66 ##STR79##

To a solution of 4.14 g (10.7 mmol) of the compound of Example 65 in 40ml of MeOH, was added 13.4 ml (13.4 mmol) of 1N NaOH. The reactionmixture was refluxed for 2.5 hours, cooled and then partitioned between200 ml of 0.2N HCl and 200 ml of EtOAc. The resultant layers wereseparated and the organic layer was washed with 200 ml of brine, driedover Na₂ SO₄, filtered and then concentrated in vacuo to provide a darkyellow oil. This oil was purified using flash chromatography (SiO₂,eluent of 15% EtOAc in hexanes).

Yield: 2.9 g of a white foam (80%). m.p. 57-60° C. IR(KBr): 3444, 2936,1727 and 1682 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 8.06 (d, J=2.2 Hz, 1H);7.74 (dd, J=2.2,8.5 Hz, 1H); 7.36 (d, J=8.5 Hz, 1H); 3.66 (s, 3H); 2.70(m, 2H); 2.40 (m, 2H); 1.60-1.90 (m, 6H); 1.60 (s, 3H); 1.55 (s, 3H);1.35 (s,3H) and 1.27 (s, 3H). MS(FD): m/e 344(M+).

Elemental Analysis for C₂₁ H₂₈ O₄ : Calcd: C, 73.23; H, 8.19; Found: C,73.50; H, 8.46.

EXAMPLE 67 ##STR80##

A mixture of 500 mg (1.52 mmol) of the compound of Example 64, 620 mg(1.80 mmol) of 50% m-chloroperbenzoic acid, 5.0 mg (0.03 mmol) ofp-toluene sulfonic acid monohydrate and 5 ml of 1,2-dichloroethane wasrefluxed for 4 hours and then stirred overnight at room temperature. Themixture was diluted with 25 ml of EtOAc and washed sequentially with 25ml of 10% potassium iodide, 10% sodium thiosulfate, saturated NaHCO₃ andbrine, dried over Na₂ SO₄, filtered and then concentrated in vacuo. Thecrude material was purified by radial chromatography (eluent of 25% Et₂O in hexanes).

Yield: 30 mg (6%). IR(CHCl₃): 3020, 1723 and 1684 cm⁻¹. ¹ H NMR (300MHz, CDCl₃): δ 7.69 (d, J=3 Hz, 1H), 7.39 (d, J=9 Hz, 1H); 7.24 (d, J=3Hz, 1H); 3.67 (s, 3H); 2.84 (m, 2H); 2.25-2.42 (m, 2H); 2.31 (s, 3H);1.60-1.90 (m, 5H); 1.35 (s, 3H) and 1.28 (s, 3H). MS(FD): m/e 344(M+).

Elemental Analysis for C₂₀ H₂₄ O₅ : Calcd: C, 69.75; H, 7.02; Found: C,69.77; H, 6.92.

EXAMPLE 68 ##STR81##

The compound was prepared substantially in accordance with the proceduredetailed in Matsumoto et al., Bull. Chem. Soc. Jpn., vol. 61, pages723-727 (1988), using the compound of Example 64.

Yield: 42%. IR(CHCl₃): 3389, 2948, 1725, 1670, 1606 cm⁻¹. ¹ H NMR (300MHz, CDCl₃): δ 7.45 (d, J=3 Hz, 1H); 7.27 (d, J=9 Hz, 1H); 7.07 (dd,J=3,9 Hz, 1H); 5.20 (s, 1H); 3.66 (s, 3H); 2.65-2.80 (m, 2H); 2.27-2.42(m, 2H); 1.60-1.90 (m, 5H); 1.34 (s, 3H) and 1.25 (s, 3H). MS(FD): m/e302(M+).

Elemental Analysis for C₁₈ H₂₂ O₄ : Calcd: C, 71.50; H, 7.33; Found: C,71.22; H, 7.19.

EXAMPLE 69 ##STR82##

The compound was prepared substantially in accordance with the proceduredetailed in Matsumoto et al., Bull. Chem. Soc. Jpn., vol. 61, 723-727(1988), using the compound of Example 68.

Yield: 86%. IR (CHCl₃): 2941, 1722, 1677 and 1252 cm⁻¹. ¹ H NMR (300MHz, CDCl₃): δ 7.48 (d, J=3 Hz, 1H); 7.29 (d, J=9 Hz, 1H); 7.11 (dd,J=3,9 Hz, 1H); 3.84 (s, 3H); 3.66 (s, 3H); 2.70 (m, 2H); 2.30-2.43 (m,2H); 1.60-1.90 (m, 5H); 1.34 (s, 3H) and 1.25 (s, 3H). MS(FD): m/e316(M+).

Elemental Analysis for C₁₉ H₂₄ O₄ : Calcd: C, 72.13; H, 7.65; Found: C,72.16; H, 7.35.

EXAMPLE 70 ##STR83##

A mixture of 475 mg (1.5 mmol) of the compound of Example 60B, 425 mg(3.19 mmol) of anhydrous aluminum chloride in 15 ml of toluene wasstirred at room temperature for 2 hours, under N₂. The reaction mixturewas partitioned between toluene and 1N HCl. The resultant layers wereseparated and the organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to provide an oil. This oil waspurified using flash chromatography (SiO₂, eluent of 2% EtOAc inhexanes) to provide an oil which was crystallized from MeOH.

¹ H NMR (300 MHz, CDCl₃): δ 7.00-7.30 (m, 4H); 3.30 (s, 1.5H); 3.28 (s,1.5H); 2.90 (m, 2H); 2.30 (m, 2H); 2.00 (m, 1H); 1.40-1.80 (m, 6H); 1.30(s, 1.5H); 1.22 (s, 3H) and 1.10 (s, ##STR84##

A solution of 285 mg (2.8 mmol) of chromium trioxide in 4 ml of glacialAcOH and 1 ml of H₂ O was added drop-wise to a solution of 275 mg (1mmol) of the compound of Example 70A in 5 ml of glacial AcOH. Thereaction mixture was stirred at room temperature for 2 hours and thenpartitioned between EtOAc and brine (twice). The combined organic layerswere dried over Na₂ SO₄, filtered and then concentrated in vacuo toprovide a yellow oil. This oil was purified using flash chromatography(SiO₂, eluent of 5% EtOAc in hexanes) to provide a bright yellow solid.

Yield: 50 mg (17%). m.p. 121-123° C. IR(CHCl₃) : 3019, 2954, 1727, 1688and 1248 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃ ): δ 8.14 (d, J=8 Hz, 1H); 7.70(7, J=7 Hz, 1H); 7.47 (m, 2H); 3.73 (S, 3H); 3.39 (s, 1H); 2.64 (d, J=12Hz, 1H); 2.01-2.11 (m, 1H); 1.40-1.80 (m, 4H); 1.29 (s, 3H) and 0.69 (s,3H). MS(FD): m/e 300(M+).

Elemental Analysis for C₁₈ H₂₀ O₄ : Calcd: C, 71.98; H, 6.71; Found: C,72.10; H, 6.66. ##STR85##

The compound was isolated from the reaction mixture described in Example70B.

Yield: 136 mg of an oil (47.5%). ¹ H NMR (300 MHz, CDCl₃): δ 8.01 (m,1H); 7.55 (m, 1H); 7.30 (m, 2H); 3.30 (s, 1.5H); 3.28 (s, 1.5H); 3.10(dd, J=4.12 Hz, 0.5H): 2.70 (m, 1.5H); 2.40 (m, 2H); 1.40-1.90 (m, 5H);1.30 (s, 1.5H); 1.28 (s, 1.5H); 1.23 (s, 1.5H); 0.65 (s, 1.5H).

EXAMPLE 71 ##STR86##

A solution of 0.9 ml (17 mmol) of bromine in 30 ml of anhydrous Et₂ Owas added to a solution of 3.8 g (13.3 mmol) of the compound of Example70C in 200 ml of anhydrous Et₂ O, dropwise. The reaction mixture wasstirred at room temperature for 1 hour and then washed sequentially withH₂ O, a saturated NaHCO₃ solution and 19% sodium thiosulfate, dried overNa₂ SO₄, filtered and concentrated in vacuo to provide a residue whichwas purified using flash chromatography (eluent of 3:2 CH₂ Cl₂/hexanes).

Yield: 1.2 g of yellowish oil (25%). ¹ H NMR (300 MHz, CDCl₃): δ 8.00(dd, J=2,5 Hz, 1H); 7.60 (dt, J=2,5 Hz, 1H); 7.40 (m, 2H); 4.60 (s, 1H);3.78 (s, 3H); 3.25 (s, 1H) 2.50 (d, J=7 Hz, 1H); 1.60-1.90 (m, 5H); 1.60(s 3H); 0.57 (s, 3H). ##STR87##

The compound was isolated from the reaction mixture described in Example71A.

Yield: 1.2 g of an oil (25%). ¹ H NMR (300 MHz, CDCl₃): δ 8.01 (d, J=6Hz, 1H); 7.60 (m, 1H); 7.40 (m, 2H); 5.00 (d, J=9 Hz, 1H); 3.65 (s, 3H);3.23 (d, J=9 Hz, 1H); 2.60 (m, 1H); 2.38 (d, J=7 Hz, 1H); 1.80 (m, 4H);1.52 (s, 3H) and 1.25 (s, 3H).

EXAMPLE 72 ##STR88##

A mixture of 1.2 g (3.3 mmol) of the compound of Example 71A, 450 mg(6.9 mmol) of zinc dust, 225 mg (2.7 mmol) of NaOAc and 50 ml of glacialAcOH was refluxed for 1 hour, under N₂. After cooling, the reactionmixture was filtered and the filtrate was partitioned between Et₂ O andbrine. The resultant layers were separated and the organic layer wasdried over Na₂ SO₄, filtered and then concentrated in vacuo. The crudematerial was purified using flash chromatography (SiO₂, eluent of 10%Et₂ O in hexanes).

Yield: 897 mg of a pale yellow oil (93%). IR(CHCl₃): 3018, 1721, 1675and 1257 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 8.03 (m, 1H); 7.55 (m, 1H);7.30 (m, 2H); 3.69 (s, 3H); 3.13 (dd, J=7,19 Hz, 1H); 2.76 (dd, J=3,7Hz, 1H); 2.50 (d, J=3 Hz, 1H); 2.45 (7, J=3 Hz, 1H); 1.88 (m, 1H); 1.58(m, 4H); 1.33 (s, 3H) and 0.69 (s, 3H). MS(FD): m/e 286(M+).

Elemental Analysis for C₁₈ H₂₂ O₃ : Calcd: C, 75.50; H, 7.74; Found: C,75.75; H, 7.89.

EXAMPLE 73 ##STR89##

The compound was prepared substantially in accordance with the proceduredetailed in Example 72, using 960 mg (2.6 mnmol) of the compound ofExample 71B, 4.0 g (61.2 mmol) of zinc dust, 2.0 g (24.4 mmol) of NaOAcand 50 ml of glacial AcOH. The crude material was purified using columnchromatography.

Yield: 500 mg of an oil (67.2%). IR(CHCl₃): 3028, 1722, 1679, 1258 cm⁻¹.¹ H NMR (300 MHz, CDCl₃): δ 8.01 (d, J=8 Hz, 1H); 7.54 (7, 6 Hz, 1H);7.29 (m, 2H); 3.67 (s, 3H); 2.74 (dd, J=3,7 Hz, 2H); 2.30-2.45 (m, 2H);1.60-1.90 (m, 5H); 1.36 (s, 3H) and 1.28 (s, 3H). MS(FD): m/e 286(M+).##STR90##

The compound was isolated from the reaction mixture described in Example73A

Yield: 150 mg (21%).

EXAMPLE 74 ##STR91##

A solution of 1.54 g (5.66 mmol) of the compound of Example 70A and 1.5g of 10% Pd/C in 150 ml of triethyleneglycol dimethyl ether was refluxedfor 3 hours, under N₂. After cooling, the mixture was filtered and thefiltrate was partitioned between EtOAc and brine (three times). Theresultant layers were separated and the combined organic layers weredried over Na₂ SO₄, filtered and the concentrated in vacuo to provide1.5 g of a residue. A fraction of this residue (300 mg) was purified bychromatotron (eluent of 2% CH₂ Cl₂ in hexanes initially, followed by theaddition to the mobile phase of 50 ml of CH₂ Cl₂ after 200 ml elution,and finally 4 ml of EtOAc after 300 ml had eluted).

Yield: 29 mg ¹ H NMR (300 MHz, CDCl₃): δ 7.00-7.30 (m, 4H); 3.63 (s,3H); 2.83 (m, 2H); 2.50 (m, 3H); 2.00 (m, 2H); 1.30-1.70 (m, 3H); 1.25(s, 3H); 1.10 (m, 1H); 1.02 (s, 3H). ##STR92##

The compounds were isolated from the reaction mixture described inExample 74A.

Yield: 216 mg. ##STR93##

The compound was prepared substantially in accordance with the proceduredetailed in Example 70B, using 70 mg (0.26 mmol) of the compound ofExample 74A.

Yield: 30 mg of an off-white solid (40.3%). m.p. 143-145° C. IR(CHCl₃):2951, 1718 and 1687 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=7 Hz,1H); 7.54 (m, 1H); 7.42 (d, J=7 Hz, 1H); 7.31 (d, J=7 Hz, 1H); 3.66 (s,3H); 3.23 (dd, J=14,18 Hz, 1H); 3.00 (dd, J=3,18 Hz, 1H); 2.30-2.45 (m,2H); 2.00-2.20 (m, 2H); 1.65-1.80 (m, 1H); 1.63 (m, 1H); 1.27 (s, 3H);1.13 (s, 3H) and 1.12 (m, 1H). MS(FD): m/e 286(M+).

Elemental Analysis for C₁₈ H₂₂ O₃ : Calcd: C, 75.50; H, 7.74; Found: C,75.78; H, 7.63.

EXAMPLE 75 ##STR94##

The compounds were prepared substantially in accordance with theprocedure detailed in Example 70B, using a solution of 325 mg (1.2 mmol)of the unpurified residue from Example 74A in 5 ml of glacial AcOH Thecrude material was purified using flash chromatography (SiO₂, eluent of15% Et₂ O in hexanes).

Yield: 62 mg of an oil. ##STR95##

The compound was isolated from the reaction mixture described in Example75A.

Yield: 78 mg of an oil.

Note: The reaction mixture also provided 16 mg of the compound ofExample 74C and 75 mg of the compound of Example 70A.

EXAMPLE 76 ##STR96##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using a solution containing 140 mg (0.49 mmol)of the compounds of Example 75A in 10 ml of MeOH. The crude material waspurified using flash chromatography (SiO₂, eluent of 20% Et₂ O inhexanes).

Yield: 38 mg of a solid (26%). m.p. 139-141° C. IR(CHCl₃): 3584, 3020and 1720 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.92 (d, J=7.7 Hz, 1H); 7.56(s, 1H); 7.30 (m, 2H); 7.20 (m, 1H); 3.72 (s, 3H); 3.44 (dd, J=4.0,18.4Hz, 1H); 3.12 (dd, J=14.0,18.7 Hz, 1H); 2.35 (m, 2H); 2.03 (m, 1H);1.50-1.80 (m, 3H); 1.32 (s, 3H); 1.10 (m, 1H) and 1.02 (s, 3H). MS(FD):m/e 301(M+).

Elemental Analysis for C₁₈ H₂₃ NO₃ : Calcd: C, 71.74; H, 7.69; N, 4.65;Found: C, 71.97; H, 7.77; N, 4.39. ##STR97##

The compound was isolated from the reaction mixture described in Example76A.

Yield: 38 mg of a resin (26%). IR(CHCl₃): 3583, 3027, 2935, 1721 and1263 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃ ): δ 7.85 (d, J=8.1 Hz, 1H); 7.43 (s,1H); 7.10-7.20 (m, 3H); 3.66 (s, 3H); 2.67 (d, J=8.8 Hz, 2H); 2.28-2.37(m, 2H); 1.76 (m, 4H); 1.39 (s, 3H); 1.26 (m, 1H) and 1.14 (s, 3H).MS(FD): m/e 301(M+).

EXAMPLE 77 ##STR98##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 72.

Yield: 98%. IR(CHCl₃): 3583, 2952 and 1720 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.86 (d, J=8.8 Hz, 1H); 7.20-7.38 (m, 4H); 3.70 (s, 3H); 3.10 (dd,J=8.1,19.8 Hz, 1H); 2.53-2.64 (m, 2H); 2.47 (d, 11.4 Hz, 1H); 1.70-1.90(m, 1H); 1.40-1.60 (m, 4H); 1.19 (S, 3H) and 0.56 (s, 3H). MS(FD): m/e302 (M+).

Elemental Analysis for C₁₈ H₂₃ NO₃ : Calcd: C, 71.73; H, 7.69; N, 4.65;Found: C, 71.79; H, 7.78, N, 4.44.

EXAMPLE 78 ##STR99##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 68.

IR(KBr): 3393, 2932, 1727 and 1702 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ8.00 (brs, 1H); 7.29 (d, J=3 Hz, 1H); 7.16 (d, J=9 Hz, 1H); 6.85 (dd,J=3,9 Hz, 1H); 5.25 (brs, 1H); 3.68 (s, 3H); 2.65 (m, 2H); 2.20-2.40 (m,2H); 1.55-2.04 (m, 5H); 1.40 (s, 3H) and 1.10 (s, 3H). MS(FD): m/e 318(M+).

Elemental Analysis for C₁₈ H₂₃ O₄ : Calcd: C, 68.12; H, 7.30; N, 4.41;Found: C, 67.95; H, 7.46; N, 4.12.

EXAMPLE 79 ##STR100##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 69.

Yield: 93%. IR(KBr): 3421, 2936, 1727 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ7.37 (d, J=3 Hz, 1H); 7.29 (s, 1H); 6.92 (d, J=9 Hz, 1H); 6.91 (dd,J=3,9 Hz, 1H); 3.81 (s, 3H); 3.66 (s, 3H); 2.65 (m, 2H); 2.25-2.65 (m,2H); 1.60-1.80 (m, 5H); 1.38 (s, 3H) and 1.11 (s, 3H). MS(FD): m/e331(M+).

Elemental Analysis for C₁₉ H₂₅ NO₄ : Calcd: C, 68.86; H, 7.60; N, 4.23'Found: C, 69.10; H, 7.83; N, 4.23.

EXAMPLE 80 ##STR101##

The compound was prepared substantially in accordance with the proceduredetailed in Example 71A, using the compound of Example 69.

Yield: 74% m.p. 146-148° C. IR(KBr): 2900, 1725 and 1679 cm⁻¹. ¹ H NMR(300MHz, CDCl₃): δ 7.46 (d, J=3 Hz, 1H); 7.28 (d, J=9 Hz, 1H); 7.14 (dd,J=3,9 Hz, 1H); 4.98 (d, J=13 Hz, 1H); 3.85 (s, 3H); 3.65 (s, 3H); 3.20(d, J=13Hz, 1H); 2.35 (m, 1H); 1.70-1.90 (m, 5H); 1.50 (s, 3H); 1.26 (s,3H). MS(FD): m/e 397 (M+).

Elemental Analysis for C₁₉ H₂₃ BrO₄ : Calcd: C, 57.73; H, 5.86; Found:C, 57.78; H, 6.06.

EXAMPLE 81 ##STR102##

To a solution of 200 mg (0.506 mmol) of the compound of Example 80 in 5ml of anhydrous MeOH, was slowly added a solution of NaOMe (prepared insitu by dissolving 34 mg of Na in 1 ml of anhydrous MeOH). The reactionmixture was refluxed for 2 hours, cooled and diluted with 30 ml ofbrine, under N₂. The resulting layers were separated and the organiclayer was dried over Na₂ SO₄, filtered and concentrated to provide anoily resin which was purified using flash chromatography (gradienteluent of 0-2% EtOAc in CH₂ Cl₂).

Yield: 140 mg of a yellowish oil (88%). IR(CHCl₃) 3009, 2952, 1728 and1610 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.57 (d, J=3 Hz, 1H); 7.43 (d,J=9 Hz, 1H); 7.15 (dd, J=3,9 Hz, 1H); 6.15 (s, 1H); 3.88 (s, 3H); 3.73(s, 3H); 2.48 (d, J=13 Hz, 1H); 2.18-2.29 (m, 1H); 1.71-2.07 (m, 4H);1.56 (5, 3H) and 1.52 (s, 3H). MS(FD): m/e 314 (M+).

Elemental Analysis for C₁₉ H₂₂ O₄ ·0.25H₂ O: Calcd: C, 71.54; H, 7.05;Found: C, 71.71; H, 7.14.

EXAMPLE 82 ##STR103##

The compound was prepared substantially in accordance with the proceduredetailed in Example 81, using the compound of Example 71A.

IR(CHCl₃): 2952, 1728 and 1653 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 8.19(d, J=8 Hz, 1H); 7.57 (m, 2H); 7.41 (s, J=8 Hz, 1H); 6.62 (s, 1H); 3.65(s, 3H); 2.54 (d, J=14 Hz, 1H); 2.40 (d, J=13 Hz, 1H); 1.90-2.20 (m,1H); 1.85 (m, 1H); 1.58 (m, 1H); 1.51 (s, 3H) and 1.34 (s, 3H); 1.25 (m,1H). MS(FD): m/e 284 (M+).

Elemental Analysis for C₁₈ H₂₀ O₃ ·5H₂ O: Calcd: C, 73.74; H, 7.16;Found: C, 73.80; H, 7.15.

EXAMPLE 83 ##STR104##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 81.

Yield: 50%. IR(KBr): 3411, 2950 and 1729 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃):δ 7.42 (d, J=3 Hz, 1H); 7.34 (s, 1H); 7.31 (d, J=9 Hz, 1H); 6.96 (dd,J=3, 9 Hz, 1H); 6.80 (s, 1H); 3.84 (s, 3H); 3.71 (s, 3H); 2.40 (d, J=13Hz, 1H); 2.13-2.24 (m, 1H); 1.72-2.01 (m, 4H); 1.63 (s, 3H) and 1.40 (s,3H). MS(FD): m/e 329 (M+)

EXAMPLE 84 ##STR105##

The compound was prepared substantially in accordance with the proceduredetailed in Example 81, using the compound of Example 71B.

Yield: 47%. IR(CHCl₃): 2954, 1728 and 1653 cm⁻¹. ¹ H NMR (300 MHz,CDCl₃): δ 812 (d, J=7.7 Hz, 1H); 7.55 (m, 2H); 7.39 (s, J=7.7 Hz, 1H);6.18 (s, 1H); 3.73 (s, 3H); 2.55 (m, 1H); 2.23 (m, 1H); 1.80-2.10 (m,3H); 1.60 (m, 1H) and 1.55 (s, 6H). MS(FD): m/e 284 (M+).

Elemental Analysis for C₁₈ H₂₀ O₃ : Calcd: C, 76.03; H, 7.09; Found: C,75.77; H, 7.20.

EXAMPLE 85 ##STR106##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 82.

Yield: 58.5%. m.p. 175-180° C. IR(KBr): 3426, 2932 and 1702 cm⁻¹. ¹ HNMR (300 MHz, CDCl₃): δ 8.02 (d, J=7.3 Hz, 1H); 7.80 (s, 1H); 7.39 (m,2H); 7.32 (s, 1H); 7.23 (d, J=8.1 Hz, 1H); 3.65 (s, 3H); 2.47 (d, J=13.2Hz, 1H); 2.32 (d, J=14.3 Hz, 1H); 1.95-2.18 (m, 2H); 1.70 (m, 1H); 1.54(s, 3H); 1.28 (s, 3H) and 1.23 (m, 1H). MS(FD)m/e 299 (M+).

EXAMPLE 86 ##STR107##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 84.

Yield: 62. m.p. 131-134° C. IR(KBr): 3266, 2955 and 1722 cm⁻¹. ¹ H NMR(300 MHz, CDCl₃): δ 7.92 (d, J=7.7 Hz, 1H); 7.79 (s, 1H); 7.40 (m, 2H);7.27 (m, 1H); 6.83 (s, 1H); 3.71 (s, 3H); 2.44 (d, J=12.8 Hz, 1H);2.14-2.24 (m, 1H); 1.74-1.98 (m, 4H); 1.64 (s, 3H) and 1.42 (s, 3H).MS(FD): m/e 299 (M+).

EXAMPLE 87 ##STR108##

To a stirring solution of 70 mg (0.245 mmol) of the compound of Example73A in 20 ml of anhydrous THF, was added 32 mg (0.80 mmol) of 60% NaH onmineral oil, under N₂. The resultant mixture was stirred 15 minutesfollowed by the addition of 0.15 ml (2.25 mmol) of iodomethane, viasyringe. The reaction mixture was stirred for 3 hours, quenched by thedropwise addition of H₂ O and then partitioned between Et₂ O and H₂ O.The resultant layers were separated and the organic layer was dried overNa₂ SO₄, filtered and concentrated in vacuo to provide a residue whichwas purified by radial chromatography (eluent of 10% Et₂ O in hexanes).

Yield: 16 mg of a clear oil (22%). IR(CHCl₃): 3692, 3022, 2950, 1724 and1678 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.95 (d, J=7.7 Hz, 1H); 7.54 (s,J=8.8 Hz, 1H); 7.25 (m, 2H); 3.63 (s, 3H); 2.80 (m, 2H); 2.39 (d, J=7.7Hz, 1H); 1.70-2.05 (m, 5H); 1.43 (s, 3H); 1.28 (s, 3H) and 1.13 (d,J=6.2 Hz, 3H) MS(FD): m/e 300 (M+).

Elemental Analysis for C₁₉ H₂₄ O₃ : Calcd: C, 75.97; H, 8.05; Found: C,75.80; H, 7.96.

EXAMPLE 88 ##STR109##

A mixture of 50 mg (0.165 mmol) of the compound of Example 68, 35 mg(0.165 mmol) of carbobenzyloxyglycine, 35 mg (0.170 mmol) of1,3-dicyclohexylcarbodiimide (DCC), 2 mg (0.0165 mmol) of4-dimethylaminopyridine in 25 ml of anhydrous Et₂ O was stirred for 16hours resulting in the formation of a solid. This solid was removed byfiltration and the filtrate was washed sequentially with H₂ O, a 5% AcOHsolution and brine. The combined organic layers were dried over Na₂ SO₄,filtered and then concentrated in vacuo to provide a resin which waspurified using flash chromatography (SiO₂, eluent of 20% Et₂ O inhexanes).

Yield: 54 mg of a light yellow solid (66%). IR(KBr): 3330, 2934, 1779,1725, 1685 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 7.70 (s, 1H); 7.36 (m, 8H);6.20 (s, 2H); 4.26 (d, J=6 Hz, 2H); 3.67 (s, 3H); 2.73 (dd, J=3,6 Hz,2H); 2.40 (m, 2H); 1.50-2.00 (m, 5H); 1.35 (s, 3H); 1.28 and (s, 3H).MS(FD): m/e 494 (M+).

EXAMPLE 89 ##STR110##

The compound was prepared substantially in accordance with the proceduredetailed in Example 88, using the compound of Example 68 andN-t-butoxycarbonyl-L-alanine.

Yield: 96%. IR(CHCl₃): 3444, 2938, 1763, 1714 cm⁻¹. ¹ H NMR (300 MHz,CDCl₃ ): δ 7.69 (d, J=2.6 Hz, 1H); 7.41 (d, J=8.5 Hz, 1H); 7.30 (d,J=2.6 Hz, 1H); 5.10 (brm, 1H); 4.55 (brm, 1H); 3.65 (s, 3H); 2.73 (dd,J=3.3, 6.6 Hz, 2H); 2.32-2.42 (m, 2H); 1.70-2.20 (m, 5H); 1.55 (d,J=7.OHz, 3H); 1.47 (s, 6H); 1.43 (s, 3H); 1.35 (s, 3H) and 1.28 (s, 3H),MS(FD) m/e 474 (M+).

EXAMPLE 90 ##STR111##

A mixture of 100 mg (0.21 mmol) of the compound of Example 89 in 2 ml ofCH₂ Cl₂ was added to 2 ml of a 1:1 CH₂ Cl₂ /CF₃ COOH mixture. Afterstirring for 1 hour, the reaction mixture was concentrated in vacuo. Theresultant residue was concentrated repetitively in Et₂ O until a foamwas obtained.

Yield: 85 mg (83%). IR(CHCl₃): 2941, 1715, 1711 and 1682 cm⁻¹. ¹ H NMR(300 MHz, CDCl₃): δ 7.65 (m, 2H); 7.41 (d, J=8.1 Hz, 1H); 4.30 (m, 1H);3.62 (s, 3H); 2.63 (m, 2H); 2.25-2.40 (m, 2H); 1.60-1.90 (m, 5H); 1.34(s, 3H) and 1.24 (s, 3H); 1.22 (d, J=7.OHz, 3H). MS(FD): m/e 374, freebase (M+)

EXAMPLE 91 ##STR112##

To a solution of 550 mg (1.0 mmol) of the compound of Example 89 in 10ml of CH₂ Cl₂, was added 3 ml (39 mmol) of CF₃ COOH. After stirring for1 hour, the reaction mixture was concentrated in vacuo to provide afoam. This foam was dissolved in 20 ml of CH₂ Cl₂ followed by theaddition of 0.17 ml (1.2 mmol) of Et₃ N. The resultant layers wereseparated and the organic layer was washed with H₂ O, dried over Na₂SO₄, filtered and concentrated in vacuo to provide a foam. ##STR113##

The compound was prepared substantially in accordance with the proceduredetailed in Example 88, using the compound of Example 91A and 230 mg(1.2 mmol) of N-t-butyloxycarbonyl-L-alanine

Yield: 255 mg (47%). IR(KBr): 3334, 2938, 1770, 1725 and 1687 cm⁻¹. ¹ HNMR (300 MHz, CDCl₃): δ 7.69 (d, J=3 Hz, 1H); 7.41 (d, J=9 Hz, 1H); 7.29(d, J=3 Hz, 1H); 6.70 (m, 1H); 5.00 (m, 1H); 4.80 (m, 1H); 4.20 (m, 1H);3.67 (s, 3H); 2.73 (m, 2H); 2.36 (m, 2H); 1.60-1.90 (m, 5H); 1.58 (d,J=7 Hz, 3H); 1.45 (s, 9H); 1.38 (d, J=7 Hz, 3H); 1.35 (s, 3H) and 1.27(s, 3H) MS(FD): m/e 544 (M+).

Elemental Analysis for C₂₉ H₄₀ N₂ O₈ ·0.75H₂ O: Calcd: C, 62.40; H,7.43; N, 5.02; Found: C, 62.30; H, 7.24; N, 4.77.

EXAMPLE 92 ##STR114##

The compound was prepared substantially in accordance with the proceduredetailed in Example 90, using the compound of Example 91B.

Yield: 95%. IR(KBr): 2950, 1770 and 1681 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃):δ 8.17 (brs, 3H); 7.60 (s, 1H); 7.40 (d, J=2.6 Hz, 1H); 7.27 (m, 1H);4.65 (brs, 1H); 4.40 (brs, 1H); 3.70 (d, J=2 Hz, 1H); 3.62 (s, 3H); 2.70(m, 7H); 2.35 (m, 2H); 1.50-1.85 (m, 6H); 1.32 (s, 3H) and 1.23 (s, 3H).MS(FD): m/e 445 free base (M+).

EXAMPLE 93 ##STR115##

The compound was prepared substantially in accordance with the proceduredetailed in Example 88, using the compound of Example 68 andN-t-butoxycarbonyl-L-valine.

Yield: 47%. IR(KBr) 3377, 2969, 1766, 1724 and 1688 cm⁻¹. ¹ H NMR (300MHz, CDCl₃): δ 7.68 (d, J=2.6 Hz, 1H); 7.41 (d, J=8.8 Hz, 1H); 7.29 (d,J=2.6 Hz, 1H); 5.06 (brm, 1H); 4.45 (brm, 1H); 3.65 (s, 3H); 2.74 (dd,J=3.3,7.0 Hz, 2H); 2.30-2.43 (m, 1H); 1.70-1.90 (m, 6H); 1.48 (s, 9H);1.35 (s, 3H); 1.28 (s, 3H); 1.09 (d, J=6.6 Hz, 3H); 1.02 (d, J=7.0 Hz,3H). MS(FD): m/e 502 (M+).

Elemental Analysis for C₂₈ H₃₉ NO₇ : Calcd: C, 67.04; H, 7.84; N, 2.79;Found: C, 66.82; H, 7.73; N, 2.58.

EXAMPLE 94 ##STR116##

The compound was prepared substantially in accordance with the proceduredetailed in Example 90, using the compound of Example 93.

Yield: 99% yield. IR(KBr): 3068, 2943, 1758, 1722 and 1668 cm⁻¹. ¹ H NMR(300 MHz, CDCl₃): δ 7.68 (m, 1H); 7.40 (m, 2H); 4.08 (d, J=4.8 Hz, 1H);3.65 (s, 3H); 2.70 (m, 2H); 2.30-2.40 (m, 2H); 1.70-1.90 (m, 6H); 1.34(s, 3H); 1.26 (s, 3H); 1.16 (d, J=2.9 Hz, 3H) and 1.14 (d, J=2.9 Hz,3H). MS(FD): m/e free base 402 (M+).

Elemental Analysis for C₂₅ H₃₂ NO₇ : Calcd: C, 58.25; H. 6.26; N, 2.72;Found: C, 57.98; H, 6.32; N, 2.64.

EXAMPLE 95 ##STR117##

To a solution of 295 mg (0.98 mmol) of the compound of Example 77 in 5ml of anhydrous DMF, was added 60 mg (1.50 mmol) of 60% NaH on mineraloil, under N₂, followed by the addition of 0.18 ml (1.90 mmol) of methylbromoacetate was added by syringe. The reaction mixture was stirred for1 hour and then cautiously quenched by the dropwise addition of brineunder N₂. The reaction mixture was partitioned between brine and Et₂ O,the resulting layers were separated and the organic layer was dried overNa₂ SO₄, filtered and the concentrated in vacuo to provide an oil whichwas purified using flash chromatography (SiO₂, eluent of 20% Et₂ O inhexanes).

Yield: 175 mg of a clear oil (48%). IR(CHCl₃): 2953, 1737 and 1725 cm⁻¹.¹ H NMR (300 MHz, CDCl₃): δ 7.87 (d, J=8 Hz, 1H); 7.29 (m, 2H); 7.19 (s,J=8 Hz, 1H); 4.75 (s, 2H); 3.76 (s, 3H); 3.69 (s, 3H); 3.17 (dd, J=8,20Hz, 1H); 2.35-2.57 (m, 3H); 1.73-1.85 (m, 1H); 1.44-1.61 (m, 4H); 1.20(s, 3H) and 0.56 (s, 3H). MS(FD): m/e 373 (M+).

Elemental Analysis for C₂₁ H₂₇ NO₅ : Calcd: C, 67.54; H, 7.29; N, 3.75;Found: C, 67.84; H, 7.58; N, 3.89.

EXAMPLE 96 ##STR118##

A mixture of 56.7 mg (0.152 mmol) of the compound of Example 95, 0.2 ml(0.2 mmol) of 1N NaOH and 5 ml of MeOH was stirred at room temperaturefor 4 days and then diluted to 30 ml with brine and extracted withEtOAc. The layers were separated and the aqueous layer was acidifiedwith 5N HCl and extracted with EtOAc. The combined organic layers weredried over Na₂ SO₄, filtered and then concentrated in vacuo.

Yield: 45.7 mg of an amorphous tan resin (84%). IR(CHCl₃): 3030, 2951and 1720 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 12.75 (brs, 1H); 7.76 (d, J=8Hz, 1H); 7.40 (m, 2H); 7.21 (m, 1H); 4.66 (s, 2H); 3.62 (s, 3H); 3.05(dd, J=8,20 Hz, 1H); 2.47 (m, 3H); 1.60-1.80 (m, 1H); 1.20-1.59 (m, 4H);1.10 (s, 3H) and 0.42 (s, 3H). MS(FD): m/e 359 (M+).

Elemental Analysis for C₂₀ H₂₅ NO₅ ·0.25H₂ O: Calcd: C, 66.05; H, 7.01;N, 3.85; Found: C, 65.91; H, 7.35; N, 3.61.

EXAMPLE 97 ##STR119##

A mixture of 111.8 mg (0.31 mmol) of the compound of Example 96, 0.31 ml(0.31 mmol) of 1N NaOH and 10 ml of anhydrous CH3CN was sonicated for 30minutes and then concentrated in vacuo to provide a residue. Thisresidue was repetitively concentrated from fresh Et₂ O to provide anamorphous solid.

Yield: 116 mg (98%). IR(KBr): 3429, 2948, 1725 and 1611 cm⁻¹. ¹ H NMR(300 MHz, CDCl₃ ): δ 7.75 (d, J=7.4 Hz, 1H); 7.32 (m, 2H); 7.20 (m, 1H);4.20 (s, 2H); 3.63 (s, 3H); 3.00 (dd, J=7.7,19.1 Hz, 1H); 2.35-2.50 (m,3H); 1.60-1.80 (m, 1H); 1.40-1.60 (m, 4H); 1.10 (s, 3H) and 0.43 (s,3H). MS(FD): m/e 285 (M+-C₂ H₂ O₃ Na).

EXAMPLE 98 ##STR120##

A mixture of 4.0 g (14.7 mmol) of the compound of Example 70A and 1.2 ml(16.9 mmol) of acetyl chloride in 60 ml of carbon disulfide to asuspension of 2.6 mg (19.5 mmol) of anhydrous aluminum chloride in 100ml of carbon disulfide, via dropping funnel. The reaction mixture wasrefluxed for 1 hour and then the carbon disulfide was removed bydownward distillation. The resultant residue was cautiously quenched bythe addition of 100 ml of 0.2N HCl. The desired compound was extractedusing 100 ml of CH₂ Cl₂, dried over Na₂ SO₄, filtered and thenconcentrated in vacuo to provide a dark red oil which was purified usingflash chromatography (SiO₂, eluent of 20% Et₂ O in hexanes).

Yield: 1.7 g of an oil (87% based on recovered starting material). ¹ HNMR (300 MHz, CDCl₃): δ 7.90 (d, J=4 Hz, 1H); 7.75 (d, J=4 Hz, 0.5H);7.63 (d, J=4 Hz, 0.5H); 7.37 (d, J=6 Hz, 0.5H); 7.10 (d, J=6 Hz, 0.5H);3.70 (s, 1.5H); 3.68 (s, 1.5H); 2.92 (m, 2H); 2.60 (s, 3H); 2.00-2.50(m, 3H); 1.40-1.98 (m, 6H); 1.29 (s, 1.5H); 1.26 (s, 1.5H); 1.24 (s,1.5H) and 1.10 (s, 1.5H). ##STR121##

A mixture of 1.7 g (5.4 mmol) of the compound of Example 98A, 1.9 g (5.5mmol) of 50% 3-chloroperoxybenzoic acid, 18 mg (0.095 mmol) of p-toluenesulfonic acid monohydrate in 25 ml of 1,2-dimethyoxyethane was refluxedfor 3 hours, under N₂. After cooling, the reaction mixture was dilutedwith Et₂ O and washed sequentially with 10% potassium iodide, 10% sodiumthiosulfate, a saturated NaHCO₃ solution and brine, dried over Na₂ SO₄,filtered and then concentrated to provide a resin. This resin wasdissolved in 25 ml of MeOH and 10 ml of H₂ O containing 1.6 g (19.0mmol) of NaHCO₃. The resultant mixture was refluxed for 1.5 hours,cooled, filtered and concentrated in vacuo to provide a residue. Thisresidue was partitioned between H₂ O and Et₂ O. The resulting layerswere separated and the organic layer was washed sequentially with 1N HCland brine, dried over Na₂ SO₄, filtered and concentrated in vacuo

Yield: 1.55 g (99%). ¹ H NMR (300 MHz, CDCl₃) δ 6.85 (m, 1H); 6.70 (d,J=6 Hz, 1H); 6.55 (dd, J=6 Hz, 1H); 3.63 (s, 3H); 2.80 (m, 2H);1.90-2.30 (m, 3H); 1.40-1.88 (m, 6H); 1.25 (s, 1.5H); 1.20 (s, 1.5H);1.17 (s, 1.5H) and 1.02 (s, 1.5H). ##STR122##

To a suspension of 1.55 g (5.4 mmol) of the compound of Example 98B and275 mg (6.87 mmol) of 60% NaH on mineral oil in 50 ml of anhydrous DMF,was added 0.5 ml (7.50 mmol) of idodomethane, under N₂. The reactionmixture was stirred for 1 hour and then cautiously quenched by thedropwise addition of brine. The reaction mixture was partitioned betweenEt₂ O and brine. The resultant layers were separated and the organiclayer was dried over Na₂ SO₄, filtered and concentrated in vacuo toprovide a residue which was purified using flash chromatography (SiO₂,eluent of 20% Et₂ O in hexanes).

Yield: 1.3 g of a clear light yellow oil (88.5% based on recoveredstarting material). ¹ H NMR (300 MHz, CDCl₃): δ 7.00 (d, J=6 Hz, 1H);6.82 (m, 1H); 6.70 (m, 1H); 3.80 (s, 3H); 3.70 (s, 3H); 2.80 (m, 2H);2.00-2.40 (m, 3H); 1.40-1.90 (m, 6H); 1.25 (s, 1.5H); 1.20 (s, 3H); 1.10(s, 1.5H).

Note: The reaction mixture also contained 200 mg of the compound ofExample 98A. ##STR123##

The compound was prepared substantially in accordance with the proceduredetailed in Example 70B, using 1.3 g (4.3 mmol) of the compound ofExample 98C. The crude material was purified using flash chromatography(SiO₂, eluent of 20% Et₂ O in hexanes).

Yield: 820 mg of an oil (60.5%). ¹ H NMR (300 MHz, CDCl₃ ): δ 8.00 (m,1H); 6.80 (m, 2H); 3.87 (s, 1.5H); 3.85 (s, 1.5H); 3.63 (s, 1.5H); 3.61(s, 1.5H); 3.01 (dd, J=5, 12 Hz, 0.5H); 2.70 (m, 1.5H); 2.40 (m, 2H);1.40-1.95 (m, 5H); 1.32 (s, 1.5H); 1.30 (s, 1.5H); 1.22 (s, 1.5H); 0.65(s, 1.5H). ##STR124##

The compound was isolated from the reaction mixture described in Example98D.

Yield: 35.4 mg of an oil. ##STR125##

The compound was isolated from the reaction mixture described in Example98D.

Yield: 150 mg of an oil (10.6%). ¹ H NMR (300 MHz, CDCl₃) : δ 8.17 (d,J=6 Hz, 1H); 6.95 (m, 1H); 6.80 (m, 1H); 3.90 (s, 3H); 3.70 (s, 3H);3.36 (s, 0.5H); 2.50 (m, 1.5H); 1.80-2.10 (m, 1H); 1.42-1.80 (m, 4H);1.40 (s, 1.5H); 1.20 (s, 1.5H); 1.17 (s, 1.5H); 0.65 (s, 1.5H).##STR126##

The compound was obtained by separating the compounds (52 mg) of Example98E by radial chromatography (eluent of 15% Et₂ O in hexanes).

Yield: 20.5 mg (1.1%) (overall yield). ¹ H NMR (300 MHz, CDCl₃): δ 7.52(d, J=2 Hz, 1H); 7.21 (d, J=6 Hz, 1H); 7.10 (dd, J=2.6 Hz, 1H); 3.87 (s,3H); 3.63 (s, 3H); 3.05 (dd, J=4,12 Hz, 1H); 2.72 (m, 1H); 2.20-2.50 (m,2H); 1.80 (m, 2H); 1.40-1.60 (m, 3H); 1.30 (s, 3H) and 0.70 (s, 3H).MS(FD): m/e 316 (M+). ##STR127##

The compound was prepared substantially in accordance with the proceduredetailed in Example 71A, using 975 mg (3.08 mmol) of the compound ofExample 98D. The crude material was purified using flash chromatography(SiO₂, eluent of 15% of Et₂ O in hexanes).

Yield: 532.6 mg (44%). ¹ H NMR (300 MHz, CDCl₃) : δ 8.03 (d, J=6 Hz,1H); 6.81 (m, 2H); 4.50 (s, 1H); 3.90 (s, 3H); 3.75 (s, 3H); 3.21 (s,1H); 2.40 (m, 1H); 1.60-2.00 (m, 5H); 1.58 (s, 3H) and 0.60 (s, 3H).##STR128##

The compound was isolated from the reaction mixture described in Example98H.

Yield: 465.1 mg of an oil (38%). ¹ H NMR (300 MHz, CDCl₃). δ 8.00 (d,J=6 Hz, 1H); 6.85 (m, 2H); 4.97 (d, J=9 Hz, 1H); 3.90 (s, 3H); 3.62 (s,3H); 3.22 (d, J=9 Hz, 1H); 2.30 (m, 1H); 1.80 (m, 5H); 1.48 (s, 3H) and1.28 (s, 3H). ##STR129##

The compound was prepared substantially in accordance with the procedureof Example 72, using 532.0 mg (1.35 mmol) of the compound of Example98H.

Yield: 280 mg of a pale yellow solid (66%) m.p. 117-119° C. IR(CHCl₃):2942, 1721, 1667 and 1596 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 8.04 (d, J=9Hz, 1H); 6.83 (s, 1H) 6.80 (d, J=3 Hz, 1H).; 3.90 (s, 3H); 3.67 (s, 3H).3.02 (dd, J=7,19 Hz, 1H); 2.72 (dd, J=2,7 Hz, 1H); 2.40 (m, 2H);1.80-1.90 (m, 1H); 1.45-1.65 (m, 4H); 1.31 (s, 3H) and 0.70 (s, 3H).MS(FD): m/e 316' (M+).

Elemental Analysis for C₁₉ H₂₄ O₄ : Calcd: C, 72.13; H, 7.65; Found: C,72.43; H, 7.67. ##STR130##

The compound was prepared substantially in accordance with the proceduredetailed in Example 72 , using 465 mg (1.17 mmol) of the compound ofExample 98I.

Yield: 328 mg of a clear oil (89%). IR(CHCl₃): 2942, 1721, 1667 and 1596cm⁻¹. ¹ H NMR (300 MHz, CDCl₃ ): δ 8.04 (d, J=9.2 Hz, 1H); 6.85 (s, 1H);6.81 (d, J=2.6 Hz , 1H); 3.90 (s, 3H); 3 .66 (s, 3H); 2.70 (m, 2H); 2.30(m, 2H); 1.60-1.90 (m, 5H); 1.35 (s, 3H) and 1.26 (s, 3H). MS(FD): m/e316 (M+).

EXAMPLE 99 ##STR131##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using 465 mg (1.17 mmol) of the compound ofExample 98J.

Yield: 79%. IR(CHCl₃): 3500, 2951 and 1719 cm⁻¹. ¹ H NMR (300 MHz,CDCl₃): δ 0.81 (d, J=7 Hz, 1H); 6.82 (d, J=2 Hz, 1H); 6.78 (dd, J=2,7Hz, 1H); 3.83 (s, 3H); 3.70 (s, 3H); 3.07 (dd, J=6.12 Hz, 1H); 2.60 (m,2H); 2.40 (m, 1H), 1.80 (m, 1H); 1.40-1.60 (m, 4H); 1.20 (s, 3H) and0.60 (s, 3H). MS(FD): m/e 331 (M+).

Elemental Analysis for C₁₉ H₂₅ NO₄ : Calcd: C, 68.86; H, 7.60; N, 4.23;Found: C, 68.56; H, 7.44; N, 4.25.

EXAMPLE 100 ##STR132##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 98K.

Yield: 61%. m.p. 162-165° C. IR(CHCl₃): 3018, 2951, 1720 and 1600 cm⁻¹.¹ H NMR (300 MHz, CDCl₃): δ 7.81 (d, J=6 Hz, 1H); 6.82 (m, 3H); 3.90 (s,3H); 3.70 (s, 3H); 2.62 (d, J=6 Hz, 2H); 2.20-2.43 (m, 2H); 1.60-1.90(m, 5H); 1.40 (s, 3H) and 1.10 (s, 3H). MS(FD): m/e 331 (M+).

Elemental Analysis for C₁₉ H₂₅ NO₄ : Calcd: C, 68.86; H, 7.60; N, 4.23;Found: C, 68.79; H, 7.42; N, 4.33.

EXAMPLE 101 ##STR133##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 98G.

Yield: 90%. ¹ H NMR (300 MHz, CDCl₃): δ 7.40 (d, J=2 Hz, 1H); 7.20 (d,J=6 Hz, 1H); 6.93 (dd, J=2,6 Hz, 1H); 3.82 (s, 3H); 3.70 (s, 3H); 3.10(dd, J=5,13 Hz, 1H); 2.50-2.63 (m, 2H); 2.1 (d, J=8 Hz, 1H); 2.30 (m,1H); 1.20-1.40 (m, 4H); 1.20 (s, 3H) and 0.60 (s, 3H). MS(FD): m/e 331(M+).

EXAMPLE 102 ##STR134##

The compound of Example 70A (14.0 g) was subjected to flashchromatography (SiO₂, eluent of hexanes) to provide 12.5 g of an oil.This oil was redissolved in hexanes and allowed to stand for 16 hours ina refrigerator which resulted in the formation of a solid. This solidwas isolated by filtration (3.9 g, 14.3 mmol) and 1.0 g was dissolved in100 ml of triethylene glycol dimethyl ether containing 1.0 g of 10% Pd/Cand refluxed for 6 hours, under N₂. After cooling, the mixture wasfiltered over celite, and the filtrate was partitioned between EtOAc andH₂ O. The resultant layers were separated and the organic layer wasdried over Na₂ SO₄, filtered and concentrated in vacuo to provide aliquid. This liquid was diluted with H₂ O which resulted in theformation of a solid. This solid was isolated by filtration, dissolvedin hexanes and allowed to crystallize at room temperature.

Yield: 297 mg (1.09 mmol). ##STR135##

The compound was prepared substantially in accordance with the proceduredetailed in Example 98A, using the compound of Example 102A.

Yield: 330 mg (98%). ##STR136##

The compound was prepared substantially in accordance with the proceduredetailed in Example 98B, using the compound of Example 102B.

Yield: 300 mg (99%). ##STR137##

The compound was prepared substantially in accordance with the proceduredetailed in Example 98C, using the compound of Example 102C.

Yield: 239 mg (76%). ##STR138##

The compound was prepared substantially in accordance with the proceduredetailed in Example 70B, using the compound of Example 102D.

Yield: 153 mg of a white solid (61%). m.p. 107-108° C. IR(KBr): 2943,1724, 1681 and 1591 cm⁻¹. ¹ H NMR (300 MHz, CDCl₃): δ 8.06 (d, J=8.5 Hz,1H); 6.88 (d, J=2.2 Hz, 1H); 6.83 (dd, J-2.2,8.5 Hz, 1H); 3.84 (s, 3H);3.70 (s, 3H); 3.19 (m, 1H); 2.95 (dd, J=3.3,18.0 Hz, 1H); 2.33 (brd,J=11.0 Hz, 2H); 2.05 (m, 2H); 1.70 (m, 1H); 2.57 (m, 1H); 1.25 (s, 3H);1.12 (m, 1H) and 1.10 (s, 3H). MS(FD): m/e 316 (M+).

Elemental Analysis for C₁₉ H₂₄ O₄ : Calcd: C, 72.13; H, 7.65; Found: C,72.13; H, 7.45.

EXAMPLE 103 ##STR139##

The compound was prepared substantially in accordance with the proceduredetailed in Example 62, using the compound of Example 102E. The crudematerial was purified by recrystallization form Et₂ O/hexanes.

Yield: 84%. m.p. 172-174° C. IR(KBr): 3286, 2959, 1721 and 1603 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, J=6 Hz, 1H); 6.84 (d, J=2 Hz, 1H);6.78 (dd, J=2.6 Hz, 1H); 3.80 (s, 3H); 3.65 (s, 3H); 3.43 (dd, J=3.12Hz, 1H); 3.10 (m, 1H); 2.30 (d, J=8 Hz, 2H); 2.00 (m, 1H); 1.70 (m, 2H);1.50 (m, 1H); 1.30 (s, 3H); 1.10 (m, 1H) and 1.00 (s, 3H). MS(FD): m/e331 (M+).

Elemental Analysis for C₁₉ H₂₅ NO₄ : Calcd: C, 68.86; H, 7.60; N, 4.23;Found: C, 69.09; H, 7.55; N, 4.38.

As noted above, the compounds of the present invention are useful forinhibiting an envelope virus that undergoes hemagglutinin-mediatedfusion with a host cell. An embodiment of the present invention is amethod of treating or preventing a viral infection where the virus is anenvelope virus that undergoes hemagglutinin-mediated fusion with a hostcell which comprises administering to a virus infected cell, a cellsusceptible of infection or a mammal in need thereof an effective amountof a compound of formula I or a pharmaceutically acceptable saltthereof. Another embodiment of the present invention is a method oftreating or preventing the symptoms associated with a viral infectioncomprising administering to a mammal in need thereof an effective amountof a compound of formula I or a pharmaceutically acceptable saltthereof. A further embodiment of the present invention is a method ofinhibiting viral replication comprising administering to avirus-infected cell, a cell susceptible to infection or a mammal in needthereof, anr effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The term "effective amount" as used herein, means an amount of acompound of the present invention which is capable of inhibiting thehemagglutinin-mediated viral fusion with the host cell. The viralinhibition contemplated by the present method includes both therapeuticand prophylactic treatment, as appropriate. The specific dose ofcompound administered according to this invention to obtain therapeuticand/or prophylactic effects will, of course, be determined by theparticular circumstances surrounding the case, including, for example,the compound administered, the route of administration, the conditionbeing treated and the individual being treated. A typical daily dose(administered in single or divided doses) will contain a dosage level offrom about 0.01 mg/kg to about 50 mg/kg of body weight of an activecompound of this invention. Preferred daily doses generally will be fromabout 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg toabout 10 mg/kg. The compounds can be administered by a variety of routesincluding oral, rectal, transdermal, subcutaneous, intravenous,intramuscular and intranasal.

The compounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular andintranasal. The compounds of the present invention are preferablyformulated prior to administration. Therefore, another embodiment of thepresent invention is a pharmaceutical formulation comprising aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier,diluent or excipient therefor.

The active ingredient in such formulations comprises from 0.1% to 99.9%by weight of the formulation. By "pharmaceutically acceptable" it ismeant that the carrier, diluent or excipient is compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

The present pharmaceutical formulations are prepared by known proceduresusing known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be admixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be asolid, semi-solid or liquid material which acts as a vehicle, excipientor medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as asolid or in a liquid medium), ointments containing, for example, up to10% by weight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, sterile packaged powdersand the like.

The following experiments were carried out to demonstrate the ability ofthe compounds of the present invention to inhibit influenza.

In vitro CPE/XTT Assay

MDCK cells were dispersed in a microtiter plate (96 wells) at 10,000cells per well with Medium 199 containing Earl's balanced salt solution(EBSS), 1% fetal bovine serum (FBS), penicillin (100 units/ml) andstreptomycin (100 μg/ml). After standing overnight at 37° C. in a carbondioxide (CO₂) incubator, the MDCK cells were infected with ˜0.1 moi(mutiplicity of infection) of influenza virus (i.e. A/Kawasaki/89 orB/Hong Kong and B/Great Lakes) at 0.03 moi. After allowing the virus toadsorb to the cells for 1-2 hours, medium containing serial dilutions ofdrug or medium alone was added to the wells. The resultant mixtures wereincubated for 2-3 days (until extensive cpe was apparent in medium alonewells). The antiviral effect of a test compound was assessed byperforming the following XTT assay.

A fresh solution (0.4 mg/ml) of XTT[2,3-bis(methoxy-4-nitro-5-sulfophenyl)-2H-tetraazolium-5-carboxanilide,inner salt, sodium salt] in warm medium without FBS was prepared. Foreach 5 ml of the XTT solution, 25 μl of 5 mM PMS (phenazinemethosulfate) in phosphate buffer saline was added. After withdrawingthe cultured supernatant, 100 μl of the freshly prepared XTT/PMS mixturewas added to each of the microtiter wells. The wells were then incubatedat 37° C. (under CO₂) for 3-4 hours or until color change is prominent.The absorbance at 450 nm (ref. 650 nm) was read in a spectrophotometer.The concentration of test compound required to cause 50% cytotoxiceffect (TC₅₀) relative to a control with no drug and no virus presentand which inhibits the development of virus cytopathic effect (cpe) by50% (IC₅₀) or 90% (IC₉₀) was determined from the linear portion of eachdose response curve.

Using this CPE/XTT assay, the IC₅₀ of the compounds of formula I wasdetermined to be in the range of 0.01-32.0 μg/ml for influenzaA/Kawasaki/89 and in the range of 0.7-97.0 μg/ml for influenza B/GreatLakes.

Plaque Reduction Assay

Susceptible MDCK cells were grown in 6 well tissue culture treatedcluster plates at 1×10⁶ cells/well in Minimum 199 with 1 percent fetalbovine serum, penicillin (100 units/ml) and streptomycin (100 μg/ml).After overnight incubation at 37° C., the growth medium was removed and0.2 ml/well of an appropriate dilution of virus was added. Afteradsorption for 1-2 hour at room temperature, the infected cell sheet wasoverlaid with equal parts of 1.5% sterile agarose solution and a twofoldconcentration of medium 199 (with 2% fetal bovine serum, 100 units/ml ofpenicillin and 100 μg/ml streptomycin) containing varying concentrationsof compounds.

The compounds were dissolved in DMSO at a concentration of 20 mg/ml andan aliquot was diluted to the desired concentration in DMSO and thenadded to the agar medium mixture. The plates were incubated in a CO₂incubator at 37° C. until the DMSO control wells contained plaques ofoptimal size. Then, a solution containing 10 percent formalin and 2percent sodium acetate was added to each well to inactivate the virusand fix the cell sheet to the plastic surface The fixed cell sheets werestained with 0.5 percent crystal violet and the plaques were counted.Results from duplicate wells at each concentration were averaged andcompared with DMSO control wells. The inhibition of plaque formation by50 or 90 percent (IC₅₀ or IC₉₀) was calculated from the linear region ofthe inhibition concentration curve using the method of Reed and Muench,Am. J. Hyg., vol. 27, pages 493-497 (1958).

Using the plaque reduction assay, the IC₅₀ of the compounds of formula Iwas determined to be in the range of 0.006-100.0 μg/ml for influenzaa/kawasaki and in the range of 1.47-100.0 μg/ml for influenza b/greatlakes.

What is claimed is:
 1. A method of inhibiting an envelope virus selectedfrom the group consisting of influenza, bovine diarrheal, hepatitis Cand tick borne encephalitis virus that undergoes hemagglutinin-mediatedfusion with a host cell which comprises administering to avirus-infected cell, a cell susceptible of infection or a mammal in needthereof, an effective amount of a compound of formula I ##STR140##wherein: R is hydrogen or R and R⁶ combine to form a bond;R⁰ and R¹ areindependently hydrogen, hydroxy, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, hydroxy(C₁-C₆ alkyl), sulfhydryl, sulfamyl, --SO₂ --Cl, --S--C(O)--N(CH₃)₂, amino,C₁ -C₄ alkylamino, di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkylsulfonylalmino, di(C₁ -C₄ alkylsulfonyl)amino --X⁰ --O--C(O)--C₁ -C₄ alkyl, --O--(X¹)_(i)--X², --C(O)--X³, --N--C(O)--R² or --O--R³ ; X⁰ is a bond or divalent(C₁-C₆ alkyl); X¹ is an amino acid; X² is hydrogen or an amino protectinggroup; i is 1, 2 or 3; X³ is C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halo(C₁ -C₆alkyl), hydroxy(C₁ -C₆ alkyl) or phenyl; R² is C₁ -C₄ alkyl, C₁ -C₄alkoxy, halo(C₁ -C₄ alkyl), hydroxy(C₁ -C₄ alkyl), phenyl,p-methoxy-phenyl, p-fluoro-phenyl, naphthyl, pyridyl, piperidinyl,thiazolyl, oxazolyl, thienyl, furyl, tetrahydrofuryl or cyclohexyl; R³is C₁ -C₆ alkenyl, --CH₂ --R^(3a), --C(O)--R^(3b), --C(S)--R^(3c),--C(CH₃)₂ C(O)NH₂, phenyl or a group of the formula: ##STR141## R^(3a)is phenyl, p-fluorophenyl, pyridyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, N--(C₁ -C₄ alkoxycarbonyl)piperidinyl,N-(trifluoromethyl)-piperidinyl, thiazolyl, oxazolyl, imidazolyl,isothiazolyl, isooxazolyl, quinolyl, isoquinolyl, thienyl, furyl,tetrahydrothienyl, tetrahydrofuryl, cyclohexyl, cyclopentyl, cyclopropylor naphthyl; R^(3b) is pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, N--(C₁ -C₄ alkoxycarbonyl)piperidinyl,N-(trifluoromnethyl)piperidinyl, benzyloxy, pyridylmethyloxy, C₁ -C₆alkoxy, halo(C₁ -C₄ alkoxy), amino, C₁ -C₄ -alkylamino or di(C₁ -C₄alkyl)amino; R^(3c) is amino, C₁ -C₄ alkylamino Or di(C₁ -C₄alkyl)amino; R^(3d) is oygen, hydroximo, hydrazino or ═CHZ; Z ishydrogen, C₁ -C₄ alkyl, halogen, di(C₁ -C₄ alkyl)amino, C₁ -C₄alkoxycarbonyl, carbamoyl (C₁ -C₄ alkyl), N--(C₁ -C₄ alkyl)carbamoyl orN,N-di(C₁ -C₄ alkyl)carbamoyl: R^(3e) is hydrogen, nitro ortrifluoromethyl; X is a bond or --(CH₂)--, R⁴ is hydrogen, hydroxy,amino, C₁ -C₄ alkylamino, di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkoxy, ═O,--O--S(CH₃)₂ C(CH₃)₃, C₂ -C₆ alkanoyloxy, N--(C₂ -C₆ alkanoyl)amino,═N--R⁵ or R⁴ and R⁶ combine to form a bond; R⁵ is hydroxy, amino, C₁ -C₄alkylamino, di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkoxy, pyridylmethoxy,benzyloxy, piperazinyl, N-(methyl)piperazinyl or --O--CH₂ --C(O)--R^(5a); R^(5a) is hydroxy or C₁ -C₄ alkoxy; R⁶ is hydrogen, halo, C₁ -C₄ alkylor ═O; R⁷ is hydrogen or C₁ -C₄ alkyl; R⁸ is hydroxy, halo, C₁ -C₆alkoxy, pyrrolidinyl, peridinyl, piperazinyl, 4-methyl-piperazinyl,morpholinyl or --N(R⁹)--R¹⁰ ; R⁹ is hydrogen or methyl; R¹⁰ is-(divalent C₁ -C₆ alkyl)-R^(10a) ; R^(10a) is pyridyl,with the provisothat R.sup.≢ cannot combine with both R⁴ and R to form a bond; or apharmaceutically acceptable salt thereof.
 2. A method of treating orpreventing a viral infection where the virus is an envelope virusselected from the group consisting of influenza, bovine diarrhea,heptitis C and tick borne encephalitis virus that undergoeshemagglutinin-mediated fusion with a host cell which comprisesadministering to a virus-infected cell, a cell susceptible of infectionor a mammal in need thereof, an effective amount of a compound offormula I ##STR142## wherein: R is hydrogen or R and R⁶ combine to forma bond;R⁰ and R¹ are independently hydrogen, hydroxy, C₁ -C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁ -C₆ alkyl), sulfhydryl, sulfamyl, --SO₂ --Cl,--S--C(O)--N(CH₃)₂, amino, C₁ -C₄ alkylamino, di(C₁ -C₄ alkyl)amino, C₁-C₄ alkylsulfonylamino, di(C₁ -C₄ alkylsulfonyl)amino --X⁰ --O--C(O)--C₁-C₄ alkyl, --O--(X¹)_(i) --X², --C(O)--X³, --N--C(O)--R² or --O--R³ ; X⁰is a bond or divalent(C₁ -C₆ alkyl); X¹ is an amino acid; X² is hydrogenor an amino protecting group; i is 1, 2 or 3, X³ is C₁ -C₆ alkyl C₁ -C₆alkoxy, halo(C₁ -C₆ alkyl), hydroxy(C₁ -C₆ alkyl) or phenyl; R² is C₁-C₄ alkyl, C₁ -C₄ alkoxy, halo(C₁ -C₄ alkyl), hydroxy(C₁ -C₄ alkyl),phenyl, p-methoxy-phenyl, p-fluoro-phenyl, naphthyl, pyridyl,pipridinyl, thiazolyl, oxazolyl, thienyl, furyl, tetrahydrofuryl orcyclohexyl; R³ is C₁ -C₆ alkenyl, --CH₂ --R^(3a), --C(O)--R^(3b),--C(S)--R^(3c), --C(CH₃)₂ C(O)NH₂, phenyl or a group of the formula:##STR143## R^(3a) is phenyl, p-fluorophenyl, pyridyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, N-(C₁ -C₄alkoxycarbonyl)piperidinyl, N-(trifluoromethyl)-piperidinyl, thiazolyl,oxazolyl, imidazolyl, isothiazolyl, isooxazolyl, quinolyl, isoquinolyl,thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, cyclohexyl,cyclopentyl, cyclopropyl or naphthyl; R^(3b) is pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, N-(C₁ -C₄alkoxycarbonyl)piperidinyl, N-(trifluoromethyl)piperidinyl, benzyloaxypyridylinethyloxy, C₁ -C₆ alkoxy, halo(C₁ -C₄ alkoxy), anino, C₁ -C₄alkylamino or di(C₁ -C₄ alkyl)amino; R^(3c) is amino, C₁ -C₄ alkylaminoor di(C₁ -C₄ alkyl)amino; R^(3d) is oxygen, hydroximino, hydrazino or═CHZ; Z is hydrogen, C₁ -C₄ alkyl, halogen, di(C₁ -C₄ alkyl)amino, C₁-C₄ alkoxycarbonyl, carbamoyl (C₁ -C₄ alkyl), N--(C₁ -C₄ alkyl)carbamoylor N,N-di(C₁ -C₄ alkyl) carbamoyl; R^(3e) is hydrogen, nitro ortrifluoromethyl; X is a bond or --(CH₂)--; R⁴ is hydrogen, hydroxy,amino, C₁ -C₄ alkylamino, di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkoxy, ═O,--O--S(CH₃)₂ C(CH₃)₃, C₂ -C₆ alkanoyloxy, N-(C₂ -C₆ alkanoyl)amino,═N--R⁵ or R⁴ and R⁶ combine to form a bond; R⁵ is hydroxy, amino, C₁ -C₄alkylamino, di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkoxy, pyridylmethoxy,benzyloxy, piperazinyl, N-(methyl)piperazinyl or --O--CH₂ --C(O)--R^(5a); R⁵ a is hydroxy or C₁ -C₄ alkoxy; R⁶ is hydrogen, halo, C₁ -C₄ alkylor ═O; R⁷ is hydrogen or C₁ -C₄ alkyl; R⁸ is hydroxy, halo, C₁ -C₆alkoxy, pyrrolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl,morpholinyl or --N(R⁹)--R¹⁰ ; R⁹ is hydrogen or methyl; R¹⁰ is-(divalent C₁ -C₆ alkyl)-R^(10a) ; R^(10a) is pyridyl,with the provisothat R⁶ cannot combine with both R⁴ and R to form a bond; or apharmaceutically acceptable salt thereof.
 3. The method of claim 1wherein said compound is a compound of formula I whereR⁰ is hydrogen,hydroxy, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, hydroxy(C₁ -C₆ alkyl), ---X⁰--O--C(O)--C₁ -C₄ alkyl, --O--(X¹)_(i) --X², --C(O)--X³ or --O--R³ ; R¹is hydrogen, hydroxy, C₁ -C₆ alkoxy, sulfhydryl, sulfamyl, --SO₂ --Cl,amino, di(C₁ -C₄ alkylsulfonyl)amino, --C(O)--X³, --N--C(O)--R² or--O--R³ ; X⁰ is a bond or divalent(C₁ -C₆ alkyl); X¹ is an amino acid;X² is hydrogen or an amino protecting group; i is 1 or 2; X³ is C₁ -C₆alkyl; R^(10a) is pyridyl;or a pharmaceutically acceptable salt thereof.4. The method of claim 3 wherein said compound is a compound of formulaI whereR⁰ is hydrogen, hydroxy, C₁ -C₆ alkoxy, --O--(X¹)_(i) --X², --X⁰--O--C(O)--C₁ -C₄ alkyl or --O--R³ ; R¹ is hydrogen, hydroxy, C₁ -C₆alkoxy or --O--R³ ; X⁰ is a bond; X¹ is an amino acid; X² is hydrogen oran amino protecting group; i is 1 or 2; R³ is C₁ -C₆ alkenyl, --CH₂--R^(3a) or --C(O)--R^(3b) ; R^(3a) is p-fluorophenyl or pyridyl; R^(3b)is piperidinyl; R⁴ is hydrogen, hydroxy, ═O or ═N--R⁵ ; R⁵ is hydroxy,dimethylamino or N-(methyl) piperazinyl; R⁶ is hydrogen, bromo or ═O; R⁷is methyl; and R⁸ is methoxy;or a pharmaceutically acceptable saltthereof.
 5. The method of claim 4 wherein said compound is a compound offormula I whereR is hydrogen; R⁰ is hydrogen, hydroxy, C₁ -C₄ alkoxy,--O--(X¹)_(i) --X², --O--C(O)methyl or --O--R³ ; R¹ is hydrogen,hydroxy, C₁ -C₄ alkoxy or --O--R³ ; X¹ I is glycine, alanine or valine;R² is hydroxy(C₁ -C₄ alkyl); R³ is C₁ -C₆ alkenyl, --CH₂ --R^(3a),--C(O)--R^(3b), --C(S)--R^(3c), --C(CH₃)₂ C(O)NH₂ or a group of theformula: ##STR144## R^(3a) is phenyl, p-fluorophenyl, pyridyl,piperidinyl, piperazinyl or morpholinyl; R^(3b) is piperidinyl,piperazinyl, morpholinyl, N--(C₁ -C₄ alkoxycarbonyl)piperidinyl,N-(trifluoromethyl)piperidinyl, halo(C₁ -C₄ alkoxy) or di(C₁ -C₄alkyl)amino; R^(3c) is di(C₁ -C₄ alkyl)amino; R^(3d) is oxygen orhydroximino; R^(3e) is hydrogen, nitro or trifluoromethyl; X is a bond;R⁴ is hydrogen, hydroxy, amino, ═O, C₂ -C₆ alkanoyloxy, ═N--R⁵,--OSi(CH₃)₂ or R⁴ and R⁶ combine to form a bond; R⁵ is hydroxy, amino,di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkoxy, pyridylmethoxy,N-(methyl)piperazinyl or --O--CH₂ --C(O)--R^(5a) ; R⁶ is hydrogen,chloro, bromo, methyl or ═O; R⁷ is hydrogen or methyl; R⁸ is hydroxy,chloro, methoxy, 4-methylpiperazinyl or --N(R⁹)--R¹⁰ ; R⁹ is hydrogen;R¹⁰ is --CH₂ --R^(10a) ; and X² is hydrogen, t-butoxycarbonyl orbenzyloxycarbonyl; R⁴ is ═O or ═N--R⁵ ; R⁵ is hydroxy; R⁶ is hydrogen;ora pharmaceutically acceptable salt thereof.
 6. The method of claim 2wherein said compound is a compound of formula I whereR⁰ is hydrogen,hydroxy, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, hydroxy(C₁ -C₆ alkyl), --X⁰--O--C(O)--C₁ -C₄ alkyl, --O--(X¹)_(i) --X², --C(O)--X³ or --O--R³ ; R¹is hydrogen, hydroxy, C₁ -C₆ alkoxy, sulfhydryl, sulfamyl, --SO₂ --Cl,amino, di(C₁ -C₄ alkylsulfonyl)amino, --C(O)--X³, --N--C(O)--R² or--O--R³ ; X⁰ is a bond or divalent(C₁ -C₆ alkyl); X¹ is an amino acid;X² is hydrogen or an amino protecting group, i is 1 or 2; X³ is C₁ -C₆alkyl; R² is hydroxy(C₁ -C₄ alkyl); R³ is C₁ -C₆ alkenyl, --CH₂--R^(3a), --C(O)--R^(3b), --C(S)--R^(3c), --C(CH₃)₂ C(O)NH₂ or a groupof the formula: ##STR145## R^(3a) is phenyl, p-fluorophenyl, pyridyl,piperidinyl, piperazinyl or morpholinyl; R^(3b) is piperidinyl,piperazinyl, morpholinyl, N-(C₁ -C₄ alkoxycarbonyl)piperidinyl,N-(trifluoromethyl)piperidinyl, halo(C₁ -C₄ alkoxy) or di(C₁ -C₄alkyl)amino; R^(3c) is di(C₁ -C₄ alkyl)amino; R^(3d) is oxygen orhydroximino; R^(3e) is hydrogen, nitro or trifluoromethyl; X is a bond;R⁴ is hydrogen, hydroxy, amino, ═O, C₂ -C₆ alkanoyloxy, ═N--R⁵,--OSi(CH₃)₂ or R⁴ and R⁶ combine to form a bond; R⁵ is hydroxy, amino,di(C₁ -C₄ alkyl)amino, C₁ -C₄ alkoxy, pyridylmethoxy,N-(methyl)piperazinyl or --O--CH₂ --C(O)--R^(5a) ; R⁶ is hydrogen,chloro, bromo, methyl or ═O; R⁷ is hydrogen or methyl; R⁸ is hydroxy,chloro, methoxy, 4-methylpiperazinyl or --N(R⁹)--R¹⁰ ; R⁹ is hydrogen;R¹⁰ is --CH₂ --R^(10a) ; and R^(10a) is pyridyl.
 7. The method of claim6 wherein said compound is a compound of formula I whereR⁰ is hydrogen,hydroxy, C₁ -C₆ alkoxy, --O--(X¹)_(i) --X², --X⁰ --O--C(O)--C₁ -C₄ alkylor --O--R³ ; R¹ is hydrogen, hydroxy, C₁ -C₆ alkoxy or --O--R³ ; X⁰ is abond; X¹ is an amino acid; X² is hydrogen or an amino protecting group;i is 1 or 2; R³ is C₁ -C₆ alkenyl, --CH₂ --R^(3a) or --C(O)--R^(3b) ;R^(3a) is p-fluorophenyl or pyridyl; R^(3b) is piperidinyl; R⁴ ishydrogen, hydroxy, ═O or ═N--R⁵ ; R⁵ is hydroxy, dimethylamino orN-(methyl)piperazinyl; R⁶ is hydrogen, bromo or ═O; R⁷ is methyl; and R⁸is methoxy;or a pharmaceutically acceptable salt thereof.
 8. The methodof claim 7 wherein said compound is a compound of formula I whereR ishydrogen; R⁰ is hydrogen, hydroxy, C₁ -C₄ alkoxy, --O--(X¹)_(i) --X²,--O--C(O)methyl or --O--R³ ; R¹ is hydrogen, hydroxy, C₁ -C₄ alkoxy or--O--R³ ; X¹ is glycine, alanine or valine; X² is hydrogen,t-butoxycarbonyl or benzyloxycarbonyl; R⁴ is ═O or ═N--R⁵ ; R⁵ ishydroxy; R⁶ is hydrogen;or a pharmaceutically acceptable salt thereof.